Activation of anterior HOX genes in hindbrain development during early embryogenesis (Homo sapiens)

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3, 5, 11, 14, 16...60494, 17, 621, 9, 12, 1552, 5726, 36, 39, 45, 637, 8, 20, 3529, 32, 52, 571, 12, 15, 18, 39...39, 4139, 414952, 57, 672, 32236, 26, 41, 45, 6110, 29, 32, 654939, 4118, 21, 26, 33, 39...39, 4122, 52, 576338, 39, 4926, 36, 39, 41, 4558276734, 39, 41, 43, 527, 8, 20, 26, 33...38, 49cytosolnucleoplasmPOLR2J HIST1H2BH H2BFS HOXB1:PBX1:PKNOX1and MEIS1 at activeHOXB1 chromatinHIST1H2BJ WDR5 H2AFZ H2BFS H2BFS HIST1H2BJ HIST1H2AB HIST3H2BB KMT2D HIST1H2BK POLR2K CTCF POLR2C HOXB3 genePKNOX1 HIST2H2BE HIST2H2BE Me3K5-H3F3A HOXB4 geneMe3K5-HIST1H3A HIST1H2BM RBBP5 Me3K5-HIST2H3A HIST1H2BA HOXA2 gene HIST1H2BH H2AFJ HIST1H2AC HIST2H2AC HIST1H2AB HIST1H2AJ KMT2C HIST2H2AA3 HIST1H4 POLR2B EZH2 HIST1H2BH H2AFB1 HIST1H2BK POLR2I H2BFS HIST1H2BL Me3K5-HIST1H3A H2AFZ RARA HIST2H2AC POLR2E Me3K-28-HIST1H3A Me3K5-H3F3A HIST1H2BO RBBP7 HIST2H2BE RBBP4 HIST1H2AJ Me3K5-H3F3A HIST2H2AC H2AFV HIST1H2AJ EED Me3K5-H3F3A Me3K5-HIST2H3A POLR2K H2AFZ H2BFS HIST1H2BL HOXA3 gene H2AFZ HIST1H2BL H2BFS HIST1H2BM HIST1H2BH HIST1H2BJ HIST1H2AD HIST1H2BK RBBP5 HIST1H2BB HIST1H2AC NCOA6 POLR2I H2AFZ HIST1H2BD POLR2C POLR2A RXRA H2AFV POLR2F HIST1H2AJ HIST1H2AB PCGF2 HIST1H2BC Me3K-28-HIST2H3A HIST1H2AD HIST1H2BO Me3K-28-HIST2H3A HOXA3 gene H2AFX POLR2J H2AFX RBBP4 H2AFX NCOA6 HIST1H2BO Me3K5-HIST1H3A HIST1H2BD Me3K5-HIST1H3A HIST1H2BM HDAC3 EED HOXA3 mRNAH2AFX Me3K5-H3F3A NCOR1 MEIS1 EED POLR2I HIST1H2BH PAGR1 Me3K5-HIST2H3A Me3K5-H3F3A POLR2G Me3K-28-HIST1H3A HIST1H2AD H2AFJ HIST1H2BH HIST3H2BB HIST2H2AC HIST2H2AA3 HOXB3 activechromatinH2AFB1 KMT2D HIST1H2BD H2AFJ PAX6PAXIP1 HOXB1 mRNAHIST1H2AJ MAFB:JUN and EGR2 atactive HOXB3chromatinPOLR2L Me3K5-HIST2H3A HIST2H2AA3 HOXD4 gene H2BFS H2BFS HIST1H2BJ EED HIST1H2BL HIST1H2BN KMT2D HIST3H2BB HIST3H2BB H2AFX KDM6A HIST1H2BL POLR2K POLR2I HIST1H2AC HIST2H2AC HIST1H2BH HIST1H2BB HIST2H2BE NCOA6 HIST2H2BE HIST2H2AC HIST1H2BA HIST1H2BL Me3K5-H3F3A EGR2KDM6A POLR2C HOXB2 gene Me3K-28-HIST1H3A HIST1H2BA HOXC4 gene HIST1H4 KMT2D NCOR1 PKNOX1 POLR2G HIST1H2AD HIST1H2BB HIST1H2BA POLR2K POLR2F HIST1H2AJ POLR2H HIST2H2AC RARA POLR2H HIST2H2BE POLR2B HIST1H2AD HIST1H2AD HIST1H2BM HIST1H2BB POLR2D NCOA6 HIST3H2BB POLR2H HIST1H4 HIST1H4 HIST1H2BH RBBP7 Me3K5-HIST2H3A CNOT6 HIST1H2BN HIST1H2BM KMT2D HIST3H2BB HIST2H2AC HIST1H4 H2BFS H2AFB1 KDM6A HIST1H2BD H2BFS HIST1H2BO HIST2H2AC HIST1H2AC HIST1H2BA HIST1H2BJ RARG WDR5 POLR2F HIST1H2AJ HIST3H2BB Me3K5-HIST1H3A HIST1H2BH HIST1H2BH HIST1H2BM H2AFV HIST1H4 MAFB HIST1H4 HIST1H2BM POLR2G RBBP5 POLR2G Me3K-28-H3F3A HIST1H2AJ HIST1H2AC WDR5 HIST1H2BL HIST1H2BO HOXA2 gene Me3K5-HIST2H3A HIST1H2BL HIST1H2BN HIST1H2BC POLR2L POLR2H POLR2I Me3K5-HIST1H3A Me3K5-HIST2H3A HIST2H2AA3 HIST1H4 EP300 HIST1H2BB HIST1H2BL HIST2H2AA3 HIST1H2AB HIST1H2BO HIST1H2BK KDM6A Me3K-28-HIST2H3A POLR2B RBBP5 ASH2L H2AFB1 POLR2A HIST2H2BE POLR2L HOXB4RARB HIST1H2BM HIST1H2BN Me3K5-HIST2H3A KMT2C HIST1H2BK HIST3H2BB atRA HIST2H2AA3 HIST1H2AC RARB H2AFZ HIST1H2BB RARA,B:RXRA at HOXB4bivalent chromatinatRA HIST1H2BH Me3K-28-HIST2H3A Me3K5-HIST1H3A HIST2H2AC HIST2H2AC H2BFS HIST3H2BB POLR2L HIST2H2AC HIST1H2BN H2BFS Me3K5-HIST2H3A HOXA4 mRNAKMT2D HIST1H2BH HIST2H2AC HIST3H2BB H2BFS H2AFV H2AFJ RARA EZH2 HIST1H2BB H2AFB1 RBBP5 HIST1H2AC HOXD3 gene HIST1H2BL HIST2H2AA3 H2AFX HIST3H2BB Me3K5-H3F3A HIST1H2BH RARA,G:RXRA at HOXB1bivalent chromatinMe3K5-HIST2H3A HIST1H2AC POLR2C HIST1H2BA H2AFJ POLR2H HIST1H4 HIST1H2AC H2AFV Me3K5-HIST1H3A POLR2B RXRA KMT2D HOXD3 gene H2AFZ HIST1H2BC RXRA HIST1H2AJ HIST1H2BO WDR5 HIST1H2BL HIST2H2AC KDM6A HIST1H2BL POLR2E HIST1H2BL HIST2H2BE HIST1H2BH HIST2H2BE POLR2C Me3K-28-HIST2H3A POLR2A Me3K5-HIST2H3A HIST1H2BH POLR2H POLR2K HIST2H2AC H2AFJ HIST2H2BE HIST1H2BO KMT2D MLL2,3 complexH2AFX H2AFB1 H2AFZ HIST1H2AJ atRA:RARA,B:RXRA atactive HOXA4chromatinHIST1H2AD EZH2 POLR2G PAGR1 HIST1H2AJ PAXIP1 ASH2L HIST1H2BJ KMT2C RBBP7 HIST1H2AD Me3K5-HIST2H3A HIST1H2AB HOXB1 CNOT6:ZNF335POLR2A HIST1H2BJ HIST1H2BD HOXC4 genePOLR2B HIST2H2BE HIST2H2AA3 PAXIP1 RARA HIST1H2AB HIST1H2BH HIST1H2BJ HIST1H2BO Me3K5-HIST1H3A HOXB3 bivalentchromatinNCOA3Me3K5-HIST1H3A HIST1H2BJ HIST1H2BB H2BFS H2AFJ H2BFS HIST1H2AD HIST1H2BM HIST1H2BH H2AFZ HIST1H2BL PAXIP1 HIST2H2AA3 PBX1 HIST1H2BB NCOA6 PAXIP1 HIST1H4 HIST1H2BM EED Me3K5-HIST1H3A POLR2I HIST1H2BH HIST1H2AB HIST1H2AJ H2AFB1 H2AFX HOXD3 bivalentchromatinHIST1H2AC POLR2B H2AFZ H2AFX HIST1H2AD H2AFZ H2AFV WDR5 H2BFS HIST1H2AC HOXD1 activechromatinHIST1H2BK Me3K-28-HIST1H3A POLR2I POLR2K H2AFV PKNOX1 RBBP4 HIST1H2AJ PRC2 (EZH2) CoreASH2L HIST1H2BM HOXD4 gene EED ASH2L POLR2K Me3K5-HIST2H3A POLR2F WDR5 HIST2H2AA3 POLR2C RBBP7 H2AFB1 PAGR1 HIST1H2BH HIST1H2BO HIST1H2AC PAGR1 HIST1H2BJ H2AFB1 POLR2E PAGR1 HIST1H2BN H2AFV Me3K5-HIST1H3A Me3K5-HIST2H3A HIST1H2BA H2AFV KMT2D HIST1H2BD H2AFV HIST2H2AC Me3K5-H3F3A HIST2H2AA3 HIST3H2BB H2BFS HIST1H2BM HIST1H2BC HIST1H2BJ POLR2K HOXB1:PBX1:MEIS1,PKNOX1 at active HOXB2 chromatinHIST2H2BE ASH2L HIST1H2AB POLR2L NCOR1HIST1H2AC POLR2G HOXC4 gene HOXB2 bivalentchromatinRARA HIST1H2BN Me3K-28-H3F3A HOXA2 gene POLR2J HIST1H2BA HIST3H2BB HIST1H2BO RBBP5 RBBP5 EP300 Me3K5-HIST2H3A KMT2D POLR2E PAXIP1 HIST1H2BJ RBBP4 HIST1H2BK HIST1H2BK RBBP5 HIST1H2AB HIST1H2AJ EZH2 H2AFJ HOXB3 gene EZH2 KDM6A HIST1H2BH H2AFJ H2AFJ PBX1 SUZ12 POLR2J POLR2A HIST1H2AB PCGF2PBX1:PKNOX1Me3K5-HIST1H3A HIST1H2AD HIST1H2BJ PAXIP1 POLR2E NCOA3 PAGR1 POLR2H H2AFB1 HIST1H2AB HIST1H2BO HIST1H2BC HOXD1 gene WDR5 Me3K5-H3F3A POLR2B HIST1H2AB POLR2L Me3K5-HIST1H3A HIST1H2BL Me3K5-HIST1H3A SUZ12 HIST1H2BK HIST1H4 HIST1H2AJ H2AFJ HIST1H2BK HIST1H4 Me3K5-HIST2H3A H2AFZ HOXA1 gene HIST1H2BL ASH2L HIST1H2AD H2AFB1 POLR2C EGR2HIST3H2BB POLR2K HIST1H2BC NCOA6 RARG HIST1H2AJ POLR2E KMT2C HOXB1HIST1H2BD HIST1H2BN H2AFZ HIST1H4 H2AFZ POLR2G HIST1H2AC H2AFX HIST1H2BD HIST1H2BD POLR2H atRAHOXB1 NCOA3 HIST1H2BM HIST1H2BJ HIST1H2BA Me3K5-HIST2H3A HOXB2POLR2C H2AFZ H2AFV EGR2 HIST1H2AB KMT2C HIST1H2BA POLR2F HOXD1 geneH2BFS POLR2D HIST1H2BD Me3K-28-H3F3A HIST1H2BJ Me3K5-H3F3A HIST1H2AC RBBP4 WDR5 NCOA6 POLR2J Me3K-28-HIST1H3A HIST1H2AJ HIST1H2BC KDM6A KDM6A PKNOX1 HOXA3H2AFB1 RBBP5 POLR2G POLR2D HIST1H2BM POLR2D HIST1H2BO HIST1H2BN HIST1H2BN PAXIP1 HIST1H2BN Me3K5-H3F3A RBBP7 HIST1H4 HIST1H2BC MEIS1H2AFB1 HIST1H2BH PAX6 H2BFS RARA,G:RXRA at HOXA1bivalent chromatinH2AFB1 H2AFJ Me3K5-H3F3A H2AFX RARA,B:RXRA at HOXD4bivalent chromatinHIST1H2BA H2AFJ HIST1H2BD HIST1H2BN KDM6A HIST1H2AJ RXRA HIST1H2BA HIST1H2BB HIST1H2BK HIST1H2BJ POLR2K HIST2H2BE HIST2H2AC NCOA3 HIST2H2BE EZH2 WDR5 HIST1H2AC HIST1H2AB H2AFV HIST1H2BJ HIST1H2AD POLR2D EED HIST1H2BK HIST1H4 H2AFV HIST1H2BN PKNOX1 H2AFJ HIST1H2BO POLR2J Me3K5-HIST1H3A POLR2L HIST1H2BD HIST1H2BM HIST3H2BB Me3K5-HIST1H3A POLR2F HIST3H2BB H2AFV HIST2H2AA3 HIST1H2BK POLR2A PBX1:PKNOX1H2AFJ HIST1H2AB POLR2J HIST2H2AA3 PKNOX1 atRA:RARA,G:RXRA atactive HOXB1chromatinPOLR2J HIST1H2BM HIST1H2BC POLR2J ASH2L Me3K5-HIST2H3A SUZ12 HOXB1:PBX1:PKNOX1 atactive HOXA2chromatinHIST1H2BC H2AFJ HIST1H2BA AJUBA KMT2C HOXA2Me3K-28-HIST2H3A H2AFV HIST1H2BC EZH2 HIST1H2BD HIST1H2BD POLR2A NCOA6 RNA Polymerase IIholoenzyme complex(generic)HIST1H2AJ Me3K-28-H3F3A HIST3H2BB POLR2D ASH2L HIST1H2BD HIST1H2AD HIST1H4 H2AFB1 HIST2H2BE HIST3H2BB POLR2K H2AFJ H2AFJ CTCF PIAS2HIST1H2BK POLR2A H2AFX POLR2H HIST2H2AA3 POLR2A HOXA1 geneH2AFB1 POLR2G H2AFB1 HOXA2 mRNAH2AFB1 RXRA HIST1H2BB HIST1H2BM HIST1H2BL Me3K-28-HIST2H3A HIST2H2AA3 NCOA3 HOXA3 bivalentchromatinMe3K5-H3F3A EP300PBX1 RBBP4 RBBP4 KMT2C HIST1H2BC H2AFJ H2AFB1 HIST1H2BB HOXB2 geneHOXB3 gene ASH2L HIST3H2BB POLR2F HIST1H2BJ HOXB1 gene HIST1H2BM atRA:RARA,B:RXRA atactive HOXB4chromatinH2AFX HIST1H2BA HOXD1POLR2A H2BFS H2AFX HIST1H2BH HIST1H2BJ Me3K-28-HIST2H3A HIST1H2AC H2AFV POLR2I PAGR1 HIST2H2AC H2AFV HIST1H2AD MEIS1 HIST1H2AC HIST1H2AC POLR2I HIST1H2BN EGR2 at active HOXA2chromatinHIST2H2AC H2AFV H2AFZ EZH2 HIST2H2BE HIST2H2AA3 HIST1H2AD HIST3H2BB HIST1H2BB POLR2F HIST1H2BD HIST1H2AD EZH2 HIST1H2BK POLR2E HIST1H2AJ Me3K5-H3F3A POLR2D HOXD1 mRNARBBP4 HIST3H2BB POLR2E POLR2A EGR2RBBP4 HIST1H2BJ ZNF335 HIST2H2BE HIST2H2AC EZH2 H2AFV HIST1H2BD HIST1H2BC HIST1H2BM HIST1H2BC RARB RBBP7 RXRA HIST1H4 Me3K5-HIST1H3A HIST1H2BN HIST1H2BK KMT2D HIST1H2BA H2AFZ HIST1H2BM HIST1H2BH ASH2L HIST1H2BN H2AFB1 Me3K5-H3F3A POLR2H RXRA HOXB1 RBBP7 HIST1H2AB HIST1H2BC SUZ12 HIST3H2BB POLR2B HIST2H2BE PAXIP1 HIST1H2BL HIST1H4 Me3K5-HIST2H3A H2AFZ HIST1H2BK HIST1H2BK Me3K-28-HIST2H3A HIST1H2BA HIST1H2BC KDM6A HIST1H2BC H2AFZ HIST1H2BA CREBBPHIST1H2BD Me3K-28-H3F3A HIST1H2BC H2AFZ WDR5 HIST1H2BL HIST1H2BL HOXD4 genePBX1:PKNOX1POLR2C H2BFS HIST1H2BA H2AFX HIST1H2BD HIST1H2BB H2AFX POLR2F EGR2HOXB1 H2AFJ H2AFX POLR2I PBX1 H2AFX CTCF Me3K-28-HIST2H3A Me3K-28-H3F3A H2AFB1 HIST1H2BO EGR2 at active HOXB2chromatinHIST1H2BM H2BFS HIST1H2BM HIST1H2BL HIST1H2AC H2AFB1 Me3K5-HIST1H3A HIST1H2BO HIST1H2BH HIST1H2BC HIST1H2BH PAGR1 HIST1H2AC HIST2H2AA3 KDM6A Me3K5-H3F3A WDR5 POLR2K HIST1H2BN Me3K-28-H3F3A PAXIP1 Me3K5-HIST1H3A HIST2H2BE HIST1H2BC H2AFV NCOA6 HIST1H2BB H2AFX HOXB4 gene H2AFV H2AFV atRA HIST1H2BH POLR2F POLR2B POLR2J H2AFJ POLR2F POLR2J HOXB3HIST2H2AA3 EGR2 POLR2G H2AFZ RARA HIST1H2BC JUN HIST1H2BM HIST2H2AA3 POLR2C HOXB1 gene HIST2H2BE HIST1H2BM HIST1H2BL Me3K-28-HIST1H3A HIST1H2BK PAXIP1 HOXD3 activechromatinHOXB2 activechromatinHIST1H2BO PBX1 HIST1H2BD H2AFJ RBBP7 HOXD1 bivalentchromatinHIST1H2BA NCOA6 HIST2H2AC HIST1H2BN POLR2J HIST1H2BN HIST1H2BL HOXD4POLR2A HIST1H2AD HIST2H2AC HIST1H2AC HIST1H2BK NCOA6 H2AFX HIST1H4 POLR2B atRA HIST1H2BJ HIST2H2AA3 HIST1H2BA H2AFX HIST1H4 HIST1H2AB POLR2D KMT2C HIST1H2AC HIST2H2AC HIST3H2BB H2AFX NCOA6 POLR2B HIST2H2BE POLR2L HIST2H2BE HOXB2 gene HIST1H2BK POLR2L H2AFB1 HIST1H2BO HIST1H2AB HIST2H2AC Me3K5-HIST2H3A HIST1H2BH HOXA4PKNOX1 HIST3H2BB Me3K5-HIST1H3A H2AFZ PAGR1 HIST1H2BO RBBP5 KMT2D HIST2H2AA3 HIST1H2AB H2AFX Me3K5-HIST1H3A SUZ12 HOXB2 gene EZH2 HIST2H2BE H2AFJ EP300 H2BFS HIST1H2BL HIST1H2BN Me3K5-H3F3A H2AFX HIST1H2AD Me3K5-H3F3A HIST1H2AJ WDR5 POLR2D Me3K5-HIST1H3A POLR2J HOXA2 activechromatinRBBP7 MAFB,HOXB1:PBX1:PKNOX1at active HOXA3chromatinPOLR2C HIST1H2BJ POLR2E HIST1H2BL HIST2H2AC ASH2L SUZ12 HIST1H2AD POLR2D HOXD3 geneH2AFB1 RBBP4 H2AFJ HIST1H2BL PAGR1 PBX1 Me3K-28-H3F3A HOXC4 mRNAH2AFX HIST1H2BM HIST1H4 H2AFB1 Me3K-28-HIST1H3A HIST1H2AD HIST1H2BC HOXA2 gene MAFB Me3K-28-HIST1H3A POLR2H NCOR1 EZH2 AJUBAH2BFS EGR2 HIST1H2AC KMT2C Me3K5-H3F3A HIST1H2AD HIST1H2BK HIST1H2BC EED HIST2H2AA3 HOXB1 geneHIST1H2AD HIST1H2BC KMT2D H2AFZ HIST1H2BD POLR2H HIST1H2BO HOXC4H2BFS POLR2D HIST1H2BO HIST2H2BE Me3K-28-HIST2H3A HIST1H2AB Me3K5-HIST1H3A HIST1H2AJ RARA KMT2C POLR2L RARA HIST1H2AD Me3K5-H3F3A HIST1H4 Me3K5-HIST2H3A PAXIP1 HIST1H2BJ HIST1H2BJ PAGR1 HOXB1 gene HIST2H2AA3 HIST1H2BD POLR2I Me3K-28-H3F3A H2AFV POLR2D HIST1H4 KDM6A HIST3H2BB HIST2H2AA3 KMT2D H2AFJ HIST2H2AC HIST1H2AC EP300 H2AFJ PAXIP1 HOXA4 gene Me3K5-H3F3A HIST1H2BD HIST1H2BN HIST1H2AC POLR2C POLR2G HIST1H2AJ POLR2L POLR2H H2AFZ HIST1H2BK HIST1H2BL ASH2L HOXD3HIST2H2BE EZH2 RARB HIST1H2AB HIST1H2AC H2AFV RBBP5 CREBBP HIST2H2BE YY1 RBBP7 Me3K5-HIST2H3A SUZ12 HIST1H2AD HIST1H2AB HOXA1KMT2C HIST1H2AJ Me3K5-HIST1H3A HIST1H2BA POLR2I HIST1H2BK H2BFS HIST1H2BB H2AFZ H2AFB1 Me3K-28-H3F3A Me3K5-HIST2H3A H2AFJ HOXD4 mRNAHIST1H2BB KDM6A POLR2I HOXB4 gene NCOA6 Me3K-28-H3F3A H2AFX HIST1H2BN Me3K-28-HIST1H3A H2AFV HIST1H2BJ HIST1H2BD HIST1H2BK Me3K5-HIST2H3A H2AFJ HIST1H2BM HIST2H2AC HIST1H2BH RXRA RARG POLR2A HIST1H2AB HOXB2 gene HIST1H2BN HIST1H2AD HIST1H2AD H2AFZ HIST1H2AB KMT2C POLR2C HIST1H2AJ HIST1H2BB Me3K5-H3F3A PBX1 RBBP7 HOXC4 activechromatinNCOA6 HIST1H2AD HIST1H2BB HIST2H2BE SUZ12 POLR2B RBBP7 HOXA2 bivalentchromatinH2AFB1 Me3K5-HIST2H3A POLR2I atRA:RARA,G:RXRA atactive HOXA1chromatinKMT2C PAGR1 HIST1H2AD HIST1H4 HIST1H2BO KMT2D HOXD1 gene POLR2D HIST1H2BA Me3K5-H3F3A HIST1H2BB JUNH2AFZ H2AFZ EED RBBP5 ASH2L HIST1H2BA HIST3H2BB HIST1H2BA EED HIST1H2BH HOXA3 activechromatinH2AFB1 HOXB2 mRNAHIST1H2BK POLR2G RARA H2AFZ HIST1H2BA H2AFX HIST1H2AB Me3K5-HIST1H3A H2AFZ Me3K5-HIST2H3A HIST1H2AC Me3K5-H3F3A POLR2A HIST2H2AA3 H2AFB1 SUZ12 PBX1:PKNOX1,MEIS1H2AFX WDR5 HIST1H2AJ PAGR1 HIST2H2AA3 SUZ12 HIST1H4 HIST1H2BL POLR2G atRA H2AFJ HIST1H4 H2AFV HIST1H2AD H2AFV POLR2F Me3K5-HIST1H3A POLR2F EP300 Me3K5-HIST1H3A Me3K5-H3F3A HIST1H2BN HOXA2 geneHIST2H2AC HIST1H2BC PAGR1 HIST2H2BE HOXA3 geneHIST1H2BN HIST1H2BB H2AFJ Me3K5-HIST2H3A Me3K5-HIST2H3A POLR2G HIST1H2BK POLR2B HIST1H2BO HIST1H2BJ H2BFS HOXC4 bivalentchromatinSUZ12 PAGR1 HIST1H2BB RARG HIST1H2BH HIST1H2BD HIST1H2AC POLR2L PAXIP1 H2AFJ HIST1H2BD H2BFS HIST3H2BB HIST1H2BM POLR2B HIST1H2BA HIST1H2BC HIST1H2BL H2AFX POLR2B HIST1H2BB H2AFX HOXD3 mRNAHIST1H2AD HIST1H2AJ EED HIST1H2BD HIST2H2AA3 RBBP5 Me3K5-HIST2H3A POLR2F Me3K-28-HIST1H3A KDM6A HIST1H2BC POLR2I HIST2H2AA3 HIST1H2BO HIST2H2BE KMT2D KMT2C HIST1H2BB Me3K-28-HIST1H3A HIST1H2BB KMT2C HIST1H2AB HIST3H2BB Me3K-28-HIST2H3A HIST1H2AC HIST1H2BJ HIST1H2BM HIST1H2BD HIST1H2BO HIST1H2BA POLR2E HDAC3POLR2D HIST1H2BO HIST1H2BC POLR2E HIST2H2BE POLR2G HIST1H2AJ POLR2B NCOA3 POLR2J NCOA6 RBBP7 HOXB4 mRNAHIST1H2BH HIST1H2BD HIST2H2AC RQCD1POLR2C SUZ12 HIST1H2BD H2AFB1 HIST3H2BB H2BFS POLR2A RBBP4 HIST1H2BM POLR2K H2AFX NCOA6 H2BFS HOXA1 mRNAPAGR1 WDR5 POLR2D HIST1H2BN RBBP5 Me3K5-HIST1H3A YY1 POLR2H HIST1H4 HIST1H2AJ HIST1H2BA HIST1H4 HIST1H2BC Me3K5-HIST2H3A HIST1H2BO POLR2C POLR2J ASH2L EED KDM6A HIST1H2BK HIST1H2AB Me3K5-H3F3A POLR2C KMT2C HIST2H2BE HOXA4 gene HIST1H2BA HIST1H2AB RBBP4 PKNOX1 POLR2J POLR2E POLR2L POLR2L POLR2K HIST1H2BK RBBP4 HIST1H2BJ HIST1H2BB HIST1H2AJ HIST1H2BB H2AFV HIST1H2BO HIST1H2AB HIST1H2AC POLR2G HIST1H2BL HIST2H2AC WDR5 HIST1H2AB RXRA Me3K5-H3F3A RARA,B:RXRA at HOXA4bivalent chromatinRBBP5 HIST1H2BO KDM6A HIST1H4 HIST1H2BM Me3K5-HIST1H3A Me3K5-HIST2H3A PAXIP1 HIST1H2BA POLR2K HIST1H2BB Me3K-28-H3F3A HIST1H2BC HIST2H2AA3 atRA:RARA,B:RXRA atactive HOXD4chromatinNCOR1 HIST1H2BB HIST2H2AC POLR2K HIST1H2BD RARA HIST1H2BJ POLR2H H2AFZ SUZ12 Me3K5-H3F3A POLR2E Me3K-28-HIST1H3A POLR2F POLR2L HIST1H2BN HIST1H2BN H2AFV HIST1H4 POLR2E POLR2H HIST1H2BB POLR2E POLR2A HIST1H2BL POLR2D RBBP5 ASH2L HIST1H2BO HIST1H2BO POLR2E HIST1H2BK HIST1H2BK HIST1H2BJ HOXA4 geneHIST1H2BM HIST1H2BA HIST1H2BN Me3K5-H3F3A MEIS1 HIST2H2AA3 HIST1H4 PAXIP1 POLR2I HOXB3 gene Me3K5-HIST1H3A HIST1H2BB HIST3H2BB HIST1H2AB RARB HOXB3 mRNAHIST1H2BC RXRA POLR2F H2AFB1 HIST1H2BN H2AFV HOXA3 gene Me3K5-H3F3A HIST1H2BN EED ASH2L HIST2H2AA3 H2AFV HIST1H2BJ RARB H2BFS POLR2L HIST3H2BB HIST1H2AJ HOXA1 gene MAFBPBX1 CTCF WDR5 NCOR1 5439, 4139, 4141363639, 412739, 4139, 411, 12, 15, 18, 39...39, 4126, 41, 6113, 19, 25, 31, 4438, 39, 4934, 39, 4139, 412726, 36, 39, 4126, 36, 39, 4126, 36, 39, 63274939, 4134, 39, 4138, 39, 4939, 4139, 414939, 4139, 411, 12, 15, 18, 39...26, 41, 61


Description

In mammals, anterior Hox genes may be defined as paralog groups 1 to 4 (Natale et al. 2011), which are involved in development of the hindbrain through sequential expression in the rhombomeres, transient segments of the neural tube that form during development of the hindbrain (reviewed in Alexander et al. 2009, Soshnikova and Duboule 2009, Tumpel et al. 2009, Mallo et al. 2010, Andrey and Duboule 2014). Hox gene activation during mammalian development has been most thoroughly studied in mouse embryos and the results have been extended to human development by in vitro experiments with human embryonal carcinoma cells and human embryonic stem cells.
Expression of a typical anterior Hox gene has an anterior boundary located at the junction between two rhombomeres and continues caudally to regulate segmentation and segmental fate in ectoderm, mesoderm, and endoderm. Anterior boundaries of expression of successive Hox paralog groups are generally separated from each other by 2 rhombomeres. For example, HOXB2 is expressed in rhombomere 3 (r3) and caudally while HOXB3 is expressed in r5 and caudally. Exceptions exist, however, as HOXA1, HOXA2, and HOXB1 do not follow the rule and HOXD1 and HOXC4 are not expressed in rhombomeres. Hox genes within a Hox cluster are expressed colinearly: the gene at the 3' end of the cluster is expressed earliest, and hence most anteriorly, then genes 5' are activated sequentially in the same order as they occur in the cluster.
Activation of expression occurs epigenetically by loss of polycomb repressive complexes and change of bivalent chromatin to active chromatin through, in part, the actions of trithorax family proteins (reviewed in Soshnikova and Duboule 2009). Hox gene expression initiates in the posterior primitive streak that will contribute to extraembryonic mesoderm. Expression then extends anteriorly into the cells that will become the embryo, where expression is first observed in presumptive lateral plate mesoderm and is transmitted to both paraxial mesoderm and neurectoderm formed by gastrulation along the primitive streak (reviewed in Deschamps et al. 1999, Casaca et al. 2014).
Prior to establishment of the rhombomeres, expression of HOXA1 and HOXB1 is initiated near the future site of r3 and caudally by a gradient of retinoic acid (RA). (Mechanisms of retinoic acid signaling are reviewed in Cunningham and Duester 2015.) The RA is generated by the ALDH1A2 (RALDH2) enzyme located in somites flanking the caudal hindbrain and degraded by CYP26 enzymes expressed initially in anterior neural ectoderm of the early gastrula and then throughout most of the hindbrain (reviewed in White and Schilling 2008). HOXA1 with PBX1,2 and MEIS2 directly activate transcription of ALDH1A2 to maintain retinoic acid synthesis in the somitic mesoderm (Vitobello et al. 2011). Differentiation of embryonal carcinoma cells and embryonic stem cells in response to retinoic acid is used to model the process of differentiation in vitro (reviewed in Soprano et al. 2007, Gudas et al. 2013).
HOXA1 appears to set the anterior limit of HOXB1 expression (Barrow et al. 2000). HOXB1 initiates expression of EGR2 (KROX20) in presumptive r3. EGR2 then activates HOXA2 expression in r3 and r5 while HOXB1, together with PBX1 and MEIS:PKNOX1 (MEIS:PREP), activates expression of HOXA2 in r4 and caudal rhombomeres. AP-2 transcription factors maintain expression of HOXA2 in neural crest cells (Maconochie et al. 1999). HOXB1 also activates expression of HOXB2 in r3 and caudal rhombomeres. EGR2 negatively regulates HOXB1 so that by the time rhombomeres appear, HOXB1 is restricted to r4 and HOXA1 is no longer detectable (Barrow et al. 2000). EGR2 and MAFB (Kreisler) then activate HOXA3 and HOXB3 in r5 and caudal rhombomeres. Retinoic acid activates HOXA4, HOXB4, and HOXD4 in r7, the final rhombomere. HOX proteins, in turn, activate expression of genes in combination with other factors, notably members of the TALE family of transcription factors (PBX, PREP, and MEIS, reviewed in Schulte and Frank 2014, Rezsohazy et al. 2015). HOX proteins also participate in non-transcriptional interactions (reviewed in Rezsohazy 2014). In zebrafish, Xenopus, and chicken factors such as Meis3, Fgf3, Fgf8, and vHNF regulate anterior hox genes (reviewed in Schulte and Frank 2014), however less is known about the roles of homologous factors in mammals.
Mutations in HOXA1 in humans have been observed to cause developmental abnormalities located mostly in the head and neck region (Tischfield et al. 2005, Bosley et al. 2008). A missense mutation in HOXA2 causes microtia, hearing impairment, and partially cleft palate (Alasti et al. 2008). A missense mutation in HOXB1 causes a similar phenotype to the Hoxb1 null mutation in mice: bilateral facial palsy, hearing loss, and strabismus (improper alignment of the eyes) (Webb et al. 2012). View original pathway at:Reactome.

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Pathway is converted from Reactome ID: 5617472
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
114944view16:46, 25 January 2021ReactomeTeamReactome version 75
113062view10:59, 2 November 2020ReactomeTeamReactome version 74
112296view15:12, 9 October 2020ReactomeTeamReactome version 73
101509view11:37, 1 November 2018ReactomeTeamreactome version 66
101045view21:18, 31 October 2018ReactomeTeamreactome version 65
100576view19:52, 31 October 2018ReactomeTeamreactome version 64
100125view16:37, 31 October 2018ReactomeTeamreactome version 63
99675view15:07, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99269view12:45, 31 October 2018ReactomeTeamreactome version 62
93879view13:42, 16 August 2017ReactomeTeamreactome version 61
93446view11:23, 9 August 2017ReactomeTeamreactome version 61
87076view14:21, 18 July 2016MkutmonOntology Term : 'regulatory pathway' added !
86538view09:20, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AJUBA ProteinQ96IF1 (Uniprot-TrEMBL)
AJUBAProteinQ96IF1 (Uniprot-TrEMBL)
ASH2L ProteinQ9UBL3 (Uniprot-TrEMBL)
CNOT6 ProteinQ9ULM6 (Uniprot-TrEMBL)
CNOT6:ZNF335ComplexR-HSA-6810135 (Reactome)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
CTCF ProteinP49711 (Uniprot-TrEMBL)
EED ProteinO75530 (Uniprot-TrEMBL)
EGR2 ProteinP11161 (Uniprot-TrEMBL)
EGR2 at active HOXA2 chromatinComplexR-HSA-5617477 (Reactome)
EGR2 at active HOXB2 chromatinComplexR-HSA-5617489 (Reactome)
EGR2ProteinP11161 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
EZH2 ProteinQ15910 (Uniprot-TrEMBL)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFJ ProteinQ9BTM1 (Uniprot-TrEMBL)
H2AFV ProteinQ71UI9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
HDAC3 ProteinO15379 (Uniprot-TrEMBL)
HDAC3ProteinO15379 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HOXA1 gene ProteinENSG00000105991 (Ensembl)
HOXA1 geneGeneProductENSG00000105991 (Ensembl)
HOXA1 mRNARnaENST00000343060 (Ensembl)
HOXA1ProteinP49639 (Uniprot-TrEMBL)
HOXA2 active chromatinComplexR-HSA-6810133 (Reactome)
HOXA2 bivalent chromatinComplexR-HSA-5617490 (Reactome)
HOXA2 gene ProteinENSG00000105996 (Ensembl)
HOXA2 geneGeneProductENSG00000105996 (Ensembl)
HOXA2 mRNARnaENST00000222718 (Ensembl)
HOXA2ProteinO43364 (Uniprot-TrEMBL)
HOXA3 active chromatinComplexR-HSA-6810160 (Reactome)
HOXA3 bivalent chromatinComplexR-HSA-5617645 (Reactome)
HOXA3 gene ProteinENSG00000105997 (Ensembl)
HOXA3 geneGeneProductENSG00000105997 (Ensembl)
HOXA3 mRNARnaENST00000317201 (Ensembl)
HOXA3ProteinO43365 (Uniprot-TrEMBL)
HOXA4 gene ProteinENSG00000197576 (Ensembl)
HOXA4 geneGeneProductENSG00000197576 (Ensembl)
HOXA4 mRNARnaENST00000360046 (Ensembl)
HOXA4ProteinQ00056 (Uniprot-TrEMBL)
HOXB1 ProteinP14653 (Uniprot-TrEMBL)
HOXB1 gene ProteinENSG00000120094 (Ensembl)
HOXB1 geneGeneProductENSG00000120094 (Ensembl)
HOXB1 mRNARnaENST00000239174 (Ensembl)
HOXB1:PBX1:MEIS1,PKNOX1 at active HOXB2 chromatinComplexR-HSA-5621009 (Reactome)
HOXB1:PBX1:PKNOX1

and MEIS1 at active

HOXB1 chromatin
ComplexR-HSA-5693638 (Reactome)
HOXB1:PBX1:PKNOX1 at

active HOXA2

chromatin
ComplexR-HSA-5621001 (Reactome)
HOXB1ProteinP14653 (Uniprot-TrEMBL)
HOXB2 active chromatinComplexR-HSA-6810166 (Reactome)
HOXB2 bivalent chromatinComplexR-HSA-5617482 (Reactome)
HOXB2 gene ProteinENSG00000173917 (Ensembl)
HOXB2 geneGeneProductENSG00000173917 (Ensembl)
HOXB2 mRNARnaENST00000330070 (Ensembl)
HOXB2ProteinP14652 (Uniprot-TrEMBL)
HOXB3 active chromatinComplexR-HSA-6810168 (Reactome)
HOXB3 bivalent chromatinComplexR-HSA-5617644 (Reactome)
HOXB3 gene ProteinENSG00000120093 (Ensembl)
HOXB3 geneGeneProductENSG00000120093 (Ensembl)
HOXB3 mRNARnaENST00000311626 (Ensembl)
HOXB3ProteinP14651 (Uniprot-TrEMBL)
HOXB4 gene ProteinENSG00000182742 (Ensembl)
HOXB4 geneGeneProductENSG00000182742 (Ensembl)
HOXB4 mRNARnaENST00000332503 (Ensembl)
HOXB4ProteinP17483 (Uniprot-TrEMBL)
HOXC4 active chromatinComplexR-HSA-5617870 (Reactome)
HOXC4 bivalent chromatinComplexR-HSA-5617885 (Reactome)
HOXC4 gene ProteinENSG00000198353 (Ensembl)
HOXC4 geneGeneProductENSG00000198353 (Ensembl)
HOXC4 mRNARnaENST00000303406 (Ensembl)
HOXC4ProteinP09017 (Uniprot-TrEMBL)
HOXD1 active chromatinComplexR-HSA-5617453 (Reactome)
HOXD1 bivalent chromatinComplexR-HSA-5617473 (Reactome)
HOXD1 gene ProteinENSG00000128645 (Ensembl)
HOXD1 geneGeneProductENSG00000128645 (Ensembl)
HOXD1 mRNARnaENST00000331462 (Ensembl)
HOXD1ProteinQ9GZZ0 (Uniprot-TrEMBL)
HOXD3 active chromatinComplexR-HSA-5617663 (Reactome)
HOXD3 bivalent chromatinComplexR-HSA-5617662 (Reactome)
HOXD3 gene ProteinENSG00000128652 (Ensembl)
HOXD3 geneGeneProductENSG00000128652 (Ensembl)
HOXD3 mRNARnaENST00000249440 (Ensembl)
HOXD3ProteinP31249 (Uniprot-TrEMBL)
HOXD4 gene ProteinENSG00000170166 (Ensembl)
HOXD4 geneGeneProductENSG00000170166 (Ensembl)
HOXD4 mRNARnaENST00000306324 (Ensembl)
HOXD4ProteinP09016 (Uniprot-TrEMBL)
JUN ProteinP05412 (Uniprot-TrEMBL)
JUNProteinP05412 (Uniprot-TrEMBL)
KDM6A ProteinO15550 (Uniprot-TrEMBL)
KMT2C ProteinQ8NEZ4 (Uniprot-TrEMBL)
KMT2D ProteinO14686 (Uniprot-TrEMBL)
MAFB ProteinQ9Y5Q3 (Uniprot-TrEMBL)
MAFB,

HOXB1:PBX1:PKNOX1 at active HOXA3

chromatin
ComplexR-HSA-5617651 (Reactome)
MAFB:JUN and EGR2 at

active HOXB3

chromatin
ComplexR-HSA-5617671 (Reactome)
MAFBProteinQ9Y5Q3 (Uniprot-TrEMBL)
MEIS1 ProteinO00470 (Uniprot-TrEMBL)
MEIS1ProteinO00470 (Uniprot-TrEMBL)
MLL2,3 complexComplexR-HSA-5619379 (Reactome)
Me3K-28-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me3K-28-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
Me3K-28-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Me3K5-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me3K5-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
Me3K5-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
NCOA3 ProteinQ9Y6Q9 (Uniprot-TrEMBL)
NCOA3ProteinQ9Y6Q9 (Uniprot-TrEMBL)
NCOA6 ProteinQ14686 (Uniprot-TrEMBL)
NCOR1 ProteinO75376 (Uniprot-TrEMBL)
NCOR1ProteinO75376 (Uniprot-TrEMBL)
PAGR1 ProteinQ9BTK6 (Uniprot-TrEMBL)
PAX6 ProteinP26367 (Uniprot-TrEMBL)
PAX6ProteinP26367 (Uniprot-TrEMBL)
PAXIP1 ProteinQ6ZW49 (Uniprot-TrEMBL)
PBX1 ProteinP40424 (Uniprot-TrEMBL)
PBX1:PKNOX1,MEIS1ComplexR-HSA-5693631 (Reactome)
PBX1:PKNOX1ComplexR-HSA-5693627 (Reactome)
PCGF2 ProteinP35227 (Uniprot-TrEMBL)
PCGF2ProteinP35227 (Uniprot-TrEMBL)
PIAS2ProteinO75928 (Uniprot-TrEMBL)
PKNOX1 ProteinP55347 (Uniprot-TrEMBL)
POLR2A ProteinP24928 (Uniprot-TrEMBL)
POLR2B ProteinP30876 (Uniprot-TrEMBL)
POLR2C ProteinP19387 (Uniprot-TrEMBL)
POLR2D ProteinO15514 (Uniprot-TrEMBL)
POLR2E ProteinP19388 (Uniprot-TrEMBL)
POLR2F ProteinP61218 (Uniprot-TrEMBL)
POLR2G ProteinP62487 (Uniprot-TrEMBL)
POLR2H ProteinP52434 (Uniprot-TrEMBL)
POLR2I ProteinP36954 (Uniprot-TrEMBL)
POLR2J ProteinP52435 (Uniprot-TrEMBL)
POLR2K ProteinP53803 (Uniprot-TrEMBL)
POLR2L ProteinP62875 (Uniprot-TrEMBL)
PRC2 (EZH2) CoreComplexR-HSA-212285 (Reactome) The human Polycomb Repressive Complex 2 (PRC2) is homologous to the Drosophila PRC2. The core PRC2 contains EZH2, a histone methyltransferase specific for lysine 27 and lysine 9 of histone H3. The methyltransferase activity of EZH2 is dependent on its association with PRC2. The complex contains other uncharacterized proteins, its composition may vary in different tissues and developmental stages, and the order of assembly of the complex is presently unknown.
RARA ProteinP10276 (Uniprot-TrEMBL)
RARA,B:RXRA at HOXA4 bivalent chromatinComplexR-HSA-5617876 (Reactome)
RARA,B:RXRA at HOXB4 bivalent chromatinComplexR-HSA-5617880 (Reactome)
RARA,B:RXRA at HOXD4 bivalent chromatinComplexR-HSA-5617895 (Reactome)
RARA,G:RXRA at HOXA1 bivalent chromatinComplexR-HSA-5617465 (Reactome)
RARA,G:RXRA at HOXB1 bivalent chromatinComplexR-HSA-5617474 (Reactome)
RARB ProteinP10826 (Uniprot-TrEMBL)
RARG ProteinP13631 (Uniprot-TrEMBL)
RBBP4 ProteinQ09028 (Uniprot-TrEMBL)
RBBP5 ProteinQ15291 (Uniprot-TrEMBL)
RBBP7 ProteinQ16576 (Uniprot-TrEMBL)
RNA Polymerase II

holoenzyme complex

(generic)
ComplexR-HSA-209680 (Reactome)
RQCD1ProteinQ92600 (Uniprot-TrEMBL)
RXRA ProteinP19793 (Uniprot-TrEMBL)
SUZ12 ProteinQ15022 (Uniprot-TrEMBL)
WDR5 ProteinP61964 (Uniprot-TrEMBL)
YY1 ProteinP25490 (Uniprot-TrEMBL)
ZNF335 ProteinQ9H4Z2 (Uniprot-TrEMBL)
atRA MetaboliteCHEBI:15367 (ChEBI)
atRA:RARA,B:RXRA at

active HOXA4

chromatin
ComplexR-HSA-5617873 (Reactome)
atRA:RARA,B:RXRA at

active HOXB4

chromatin
ComplexR-HSA-5617888 (Reactome)
atRA:RARA,B:RXRA at

active HOXD4

chromatin
ComplexR-HSA-5617861 (Reactome)
atRA:RARA,G:RXRA at

active HOXA1

chromatin
ComplexR-HSA-5617448 (Reactome)
atRA:RARA,G:RXRA at

active HOXB1

chromatin
ComplexR-HSA-5617470 (Reactome)
atRAMetaboliteCHEBI:15367 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
AJUBAArrowR-HSA-5617431 (Reactome)
CNOT6:ZNF335ArrowR-HSA-5617471 (Reactome)
CREBBPR-HSA-5617896 (Reactome)
EGR2 at active HOXA2 chromatinArrowR-HSA-5617483 (Reactome)
EGR2 at active HOXA2 chromatinArrowR-HSA-5617484 (Reactome)
EGR2 at active HOXB2 chromatinArrowR-HSA-5617486 (Reactome)
EGR2 at active HOXB2 chromatinArrowR-HSA-5617492 (Reactome)
EGR2R-HSA-5617484 (Reactome)
EGR2R-HSA-5617492 (Reactome)
EGR2R-HSA-5617661 (Reactome)
EGR2TBarR-HSA-5617454 (Reactome)
EP300R-HSA-5617431 (Reactome)
EP300R-HSA-5617452 (Reactome)
EP300R-HSA-5617859 (Reactome)
EP300R-HSA-5617862 (Reactome)
EP300R-HSA-5617896 (Reactome)
HDAC3ArrowR-HSA-5617431 (Reactome)
HOXA1 geneR-HSA-5617471 (Reactome)
HOXA1 mRNAArrowR-HSA-5617471 (Reactome)
HOXA1 mRNAR-HSA-5617458 (Reactome)
HOXA1ArrowR-HSA-5617452 (Reactome)
HOXA1ArrowR-HSA-5617458 (Reactome)
HOXA2 active chromatinArrowR-HSA-6810139 (Reactome)
HOXA2 active chromatinR-HSA-5617484 (Reactome)
HOXA2 active chromatinR-HSA-5621010 (Reactome)
HOXA2 bivalent chromatinR-HSA-6810139 (Reactome)
HOXA2 geneR-HSA-5617483 (Reactome)
HOXA2 mRNAArrowR-HSA-5617483 (Reactome)
HOXA2 mRNAR-HSA-5617479 (Reactome)
HOXA2ArrowR-HSA-5617479 (Reactome)
HOXA3 active chromatinArrowR-HSA-6810161 (Reactome)
HOXA3 active chromatinR-HSA-5617641 (Reactome)
HOXA3 bivalent chromatinR-HSA-6810161 (Reactome)
HOXA3 geneR-HSA-5617676 (Reactome)
HOXA3 mRNAArrowR-HSA-5617676 (Reactome)
HOXA3 mRNAR-HSA-5617643 (Reactome)
HOXA3ArrowR-HSA-5617643 (Reactome)
HOXA4 geneR-HSA-5617877 (Reactome)
HOXA4 mRNAArrowR-HSA-5617877 (Reactome)
HOXA4 mRNAR-HSA-5617879 (Reactome)
HOXA4ArrowR-HSA-5617879 (Reactome)
HOXB1 geneR-HSA-5617454 (Reactome)
HOXB1 mRNAArrowR-HSA-5617454 (Reactome)
HOXB1 mRNAR-HSA-5617457 (Reactome)
HOXB1:PBX1:MEIS1,PKNOX1 at active HOXB2 chromatinArrowR-HSA-5617486 (Reactome)
HOXB1:PBX1:MEIS1,PKNOX1 at active HOXB2 chromatinArrowR-HSA-5621002 (Reactome)
HOXB1:PBX1:PKNOX1

and MEIS1 at active

HOXB1 chromatin
ArrowR-HSA-5617454 (Reactome)
HOXB1:PBX1:PKNOX1

and MEIS1 at active

HOXB1 chromatin
ArrowR-HSA-5693644 (Reactome)
HOXB1:PBX1:PKNOX1 at

active HOXA2

chromatin
ArrowR-HSA-5617483 (Reactome)
HOXB1:PBX1:PKNOX1 at

active HOXA2

chromatin
ArrowR-HSA-5621010 (Reactome)
HOXB1ArrowR-HSA-5617457 (Reactome)
HOXB1R-HSA-5617641 (Reactome)
HOXB1R-HSA-5621002 (Reactome)
HOXB1R-HSA-5621010 (Reactome)
HOXB1R-HSA-5693644 (Reactome)
HOXB2 active chromatinArrowR-HSA-6810159 (Reactome)
HOXB2 active chromatinR-HSA-5617492 (Reactome)
HOXB2 active chromatinR-HSA-5621002 (Reactome)
HOXB2 bivalent chromatinR-HSA-6810159 (Reactome)
HOXB2 geneR-HSA-5617486 (Reactome)
HOXB2 mRNAArrowR-HSA-5617486 (Reactome)
HOXB2 mRNAR-HSA-5617485 (Reactome)
HOXB2ArrowR-HSA-5617485 (Reactome)
HOXB3 active chromatinArrowR-HSA-6810158 (Reactome)
HOXB3 active chromatinR-HSA-5617661 (Reactome)
HOXB3 bivalent chromatinR-HSA-6810158 (Reactome)
HOXB3 geneR-HSA-5617672 (Reactome)
HOXB3 mRNAArrowR-HSA-5617672 (Reactome)
HOXB3 mRNAR-HSA-5617668 (Reactome)
HOXB3ArrowR-HSA-5617668 (Reactome)
HOXB3TBarR-HSA-5617454 (Reactome)
HOXB4 geneR-HSA-5617867 (Reactome)
HOXB4 mRNAArrowR-HSA-5617867 (Reactome)
HOXB4 mRNAR-HSA-5617881 (Reactome)
HOXB4ArrowR-HSA-5617881 (Reactome)
HOXC4 active chromatinArrowR-HSA-5617866 (Reactome)
HOXC4 active chromatinArrowR-HSA-5617887 (Reactome)
HOXC4 bivalent chromatinR-HSA-5617887 (Reactome)
HOXC4 geneR-HSA-5617866 (Reactome)
HOXC4 mRNAArrowR-HSA-5617866 (Reactome)
HOXC4 mRNAR-HSA-5617855 (Reactome)
HOXC4ArrowR-HSA-5617855 (Reactome)
HOXD1 active chromatinArrowR-HSA-5617445 (Reactome)
HOXD1 active chromatinArrowR-HSA-5617462 (Reactome)
HOXD1 bivalent chromatinR-HSA-5617445 (Reactome)
HOXD1 geneR-HSA-5617462 (Reactome)
HOXD1 mRNAArrowR-HSA-5617462 (Reactome)
HOXD1 mRNAR-HSA-5617446 (Reactome)
HOXD1ArrowR-HSA-5617446 (Reactome)
HOXD3 active chromatinArrowR-HSA-5617642 (Reactome)
HOXD3 active chromatinArrowR-HSA-5617650 (Reactome)
HOXD3 bivalent chromatinR-HSA-5617650 (Reactome)
HOXD3 geneR-HSA-5617642 (Reactome)
HOXD3 mRNAArrowR-HSA-5617642 (Reactome)
HOXD3 mRNAR-HSA-5617652 (Reactome)
HOXD3ArrowR-HSA-5617652 (Reactome)
HOXD4 geneR-HSA-5617874 (Reactome)
HOXD4 mRNAArrowR-HSA-5617874 (Reactome)
HOXD4 mRNAR-HSA-5617864 (Reactome)
HOXD4ArrowR-HSA-5617864 (Reactome)
JUNR-HSA-5617661 (Reactome)
MAFB,

HOXB1:PBX1:PKNOX1 at active HOXA3

chromatin
ArrowR-HSA-5617641 (Reactome)
MAFB,

HOXB1:PBX1:PKNOX1 at active HOXA3

chromatin
ArrowR-HSA-5617676 (Reactome)
MAFB:JUN and EGR2 at

active HOXB3

chromatin
ArrowR-HSA-5617661 (Reactome)
MAFB:JUN and EGR2 at

active HOXB3

chromatin
ArrowR-HSA-5617672 (Reactome)
MAFBR-HSA-5617641 (Reactome)
MAFBR-HSA-5617661 (Reactome)
MEIS1R-HSA-5693644 (Reactome)
MLL2,3 complexR-HSA-5617431 (Reactome)
MLL2,3 complexR-HSA-5617452 (Reactome)
MLL2,3 complexR-HSA-5617492 (Reactome)
MLL2,3 complexR-HSA-5617859 (Reactome)
MLL2,3 complexR-HSA-5617887 (Reactome)
MLL2,3 complexR-HSA-5617896 (Reactome)
MLL2,3 complexR-HSA-6810139 (Reactome)
MLL2,3 complexR-HSA-6810158 (Reactome)
MLL2,3 complexR-HSA-6810159 (Reactome)
MLL2,3 complexR-HSA-6810161 (Reactome)
MLL2,3 complexmim-catalysisR-HSA-5617431 (Reactome)
MLL2,3 complexmim-catalysisR-HSA-5617887 (Reactome)
NCOA3R-HSA-5617431 (Reactome)
NCOA3R-HSA-5617452 (Reactome)
NCOA3R-HSA-5617859 (Reactome)
NCOA3R-HSA-5617862 (Reactome)
NCOA3R-HSA-5617896 (Reactome)
NCOR1ArrowR-HSA-5617431 (Reactome)
NCOR1ArrowR-HSA-5617452 (Reactome)
NCOR1ArrowR-HSA-5617859 (Reactome)
NCOR1ArrowR-HSA-5617862 (Reactome)
NCOR1ArrowR-HSA-5617896 (Reactome)
PAX6R-HSA-5617896 (Reactome)
PBX1:PKNOX1,MEIS1R-HSA-5621002 (Reactome)
PBX1:PKNOX1R-HSA-5617641 (Reactome)
PBX1:PKNOX1R-HSA-5621010 (Reactome)
PBX1:PKNOX1R-HSA-5693644 (Reactome)
PCGF2ArrowR-HSA-5617896 (Reactome)
PIAS2ArrowR-HSA-5617454 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-5617431 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-5617445 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-5617452 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-5617650 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-5617859 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-5617862 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-5617887 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-5617896 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-6810139 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-6810158 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-6810159 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-6810161 (Reactome)
R-HSA-5617431 (Reactome) As inferred from mouse embryos and cell lines, retinoic acid binds the RARA or RARG receptor in a RAR:RXR dimer bound to the 3' region of HOXA1. Ligand binding by retinoic acid receptors causes dismissal of corepressors such as NCOR1 (Klein et al. 2000), recruitment of coactivators such as NCOA3, and alteration of chromatin at the HOXA1 gene to an active conformation. Similar activation of HOXA1 is also observed in vitro in human breast cancer cells (Chariot et al. 1995). In mouse and Xenopus Hoxa1 acts in a feedback loop to maintain retinoic acid synthesis by directly binding and activating the promoter of the Raldh2 gene.
In addition to recruiting transcription coactivators, retinoic acid also appears to affect histone modifications and DNA methylation. In human embryonal carcinoma cells, KDM6A (UTX) binds the HOXA1 gene upon retinoic acid treatment and demethylates trimethylated lysine-27 of histone H3 (H3K27me3) (Lee et al. 2007). Reduced H3K27me3 is also observed at HOXA1 in lung fibroblasts (Lan et al. 2007). Experiments with mouse embryos lacking Kdm6a and Kdm6b indicate other factors also participate in demethylation of H3K27me3 (Shpargel et al. 2014). Polycomb repressive complex 2 (PRC2), which binds H3K27me3, is also lost during activation by retinoic acid (inferred from mouse cells and also observed in human embryonal carcinoma cells, Lee et al. 2007, Sessa et al. 2007). KDM6A forms complexes with the histone methyltransferases KMT2C,D (MLL2,3) (Lee et al. 2007) which may participate in methylating histone H3 at lysine-4 (H3K4me3), an activating chromatin modification. At the 3' end of the HOXA cluster 5-methylcytosine in CG-rich regions is converted to 5-hydroxymethylcytosine by TET2 during retinoic acid induced differentiation of embryonal carcinoma cells (Bocker et al. 2012). During retinoic acid activation of HOXA genes in human monocytic leukemia cells the HOXA cluster is unfolded and its chromosomal domain is repositioned within the nucleus (Rousseau et al. 2014). Similar large-scale rearrangements may occur during embryogenesis.
In mouse embryos, expression of Hoxa1 occurs in the neural tube, adjacent mesenchyme, paraxial mesoderm, somites, and gut epithelium from rhombomere 4 to the caudal-most region of the embryo. (Rhombomeres are transiently formed segments in the neural tube that will eventually form the hindbrain.)
R-HSA-5617445 (Reactome) As inferred from the Hoxd1 homolog in mouse embryos, HOXD1 is not expressed in hindbrain. In mouse, expression of Hoxd1 begins at E8.5 in caudal lateral mesoderm. At E9.5 to E11.5 Hoxd1 expression is observed in prosomeres p2 and p3 of the diencephalon, dermatomes, urogenital tubercle, and tail bud. Expression is inducible by retinoic acid in neuroblastoma cells, however it is unknown if the induction is direct or indirect (Manohar et al. 1996, Zha et al. 2012). Nerve Growth Factor induces Hoxd1 expression in nociceptors of mouse embryos. As inferred from human posterior HOXD genes in primary human fibroblasts (Lan et al. 2007), other anterior HOX genes, and mouse Hoxd1, the activation of HOXD1 chromatin may be associated with loss of methylation at lysine-27 of histone H3 (H3K27me3) loss of polycomb repressive complex 2 (PRC2), gain of histone acetylation, and gain of methylation at histone H3K4. Like other Hox gene clusters, the HoxD cluster in mouse changes position relative to other loci in the nucleus during activation.
R-HSA-5617446 (Reactome) The HOXD1 mRNA is translated to yield HOXD1 protein.
R-HSA-5617452 (Reactome) As inferred from mouse embryos and cell lines, retinoic acid binds receptors (RARA or RARG) at retinoic acid response elements (RAREs) located 3' to the HOXB1 gene, causing recruitment of coactivators such as NCOA3 and alteration of chromatin at the HOXB1 gene to an active conformation. Similar activation of the HOXB cluster by retinoic acid is observed in human embryonal carcinoma cells (Simeone et al. 1990). In human carcinoma cells and primary fibroblasts, KDM6A (UTX) binds the HOXB1 gene upon retinoic acid treatment (Agger et al. 2007, Lee et al. 2007) and may demethylate trimethylated lysine-27 of histone H3 (H3K27me3). Reduced H3K27me3 is also observed at HOXB1 in lung fibroblasts (Lan et al. 2007). Other demethylases may be redundant with KDM6A. Polycomb repressive complex 2 (PRC2), which binds H3K27me3, is also lost during activation (Lee et al. 2007). KDM6A forms complexes with the histone methyltransferase KMT2C,D (MLL2,3) which may participate in methylating histone H3 at lysine-4 (H3K4me3), an activating chromatin modification (Lee et al. 2007). After activation by retinoic acid HOXB1 maintains its own expression by binding elements in its own promoter and activating expression (Di Rocco et al. 1997).
In mouse embryos, Hoxb1 is expressed in mesoderm and neurectoderm of primitive streak stage embryos and then becomes restricted to rhombomeres of the hindbrain. Before rhombomere formation Hoxb1 is initially expressed in the region that becomes r3-7. After rhombomere formation Hoxb1 becomes restricted to r4 and is also observed in caudal mesoderm. Hoxb1 activates expression of Egr2 (Krox20), a transcription factor that subsequently activates Hoxa2, Hoxb2, and Hoxb3 and represses Hoxb1.
R-HSA-5617454 (Reactome) After activation by retinoic acid, the HOXB1 gene is transcribed to yield mRNA (in embryos in Giampaolo et al. 1989, in human embryonal carcinoma cells in Simeone et al. 1990, Ogura and Evans 1995).
In mouse embryos, Hoxb1 is expressed in mesoderm and neurectoderm of primitive streak stage embryos and then becomes restricted to rhombomeres of the hindbrain. Before rhombomere formation Hoxb1 is initially expressed in the region that becomes r3-7. After rhombomere formation Hoxb1 becomes restricted to r4 and is also observed in caudal mesoderm.
R-HSA-5617457 (Reactome) The HOXB1 mRNA is translated to yield HOXB1 protein. The HOXB1 mRNA is a target of miR-10a (Weiss et al. 2009) and miR-196 (Yekta et al. 2008).
R-HSA-5617458 (Reactome) The HOXA1 mRNA is translated to yield HOXA1 protein (Chen et al. 2013, Chen et al. 2014). MicroRNAs miR-10a (Garzon et al. 2006), let-7c (Zhan et al. 2013), miR-99 (Chen et al. 2013) and miR-100 (Chen et al. 2014) negatively regulate translation in adult cells, however their roles in embryonic cells are unknown.
R-HSA-5617462 (Reactome) The HOXD1 gene is transcribed to yield mRNA (Manohar et al. 1996, Zha et al. 2012). The Hoxd1 homologue in mouse is expressed in caudal lateral mesoderm, prosomeres p2 and p3, dermatomes, urogenital tract, gut endoderm, and tail bud.
R-HSA-5617471 (Reactome) After activation by retinoic acid, the HOXA1 gene is transcribed to yield mRNA (inferred from mouse embryos, also demonstrated in human cancer cells, Chariot et al. 1995, Xu et al. 2014). The mRNA is a target of the microRNAs miR-10a in megakaryocytes (Garzon et al. 2006), miR210 in tumors (Huang et al. 2009), let-7c in non-small cell lung cancer cells (Zhan et al. 2013), miR-99 in epithelial cells (Chen et al. 2013), and miR-100 in tumor cells (Chen et al. 2014), however it is unknown if these play a role in embryogenesis. Opposite strand intergenic transcripts are also observed in adult tissues and placenta (Sessa et al. 2007).
In mouse embryos, expression of Hoxa1 occurs in the neural tube, adjacent mesenchyme, paraxial mesoderm, somites, and gut epithelium from rhombomere 4 to the caudal-most region of the embryo. (Rhombomeres are transiently formed segments in the neural tube that will eventually form the hindbrain.)
R-HSA-5617479 (Reactome) HOXA2 mRNA is translated to yield HOXA2 protein. The microRNA miR-3960 represses translation of HOXA2 (inferred from mouse).
R-HSA-5617483 (Reactome) The HOXA2 is transcribed to yield mRNA (in carcinoma cells, Yates et al. 2010). In mouse embryos Hoxa2 mRNA is observed in rhombomere 2 and caudally through posterior hindbrain, spinal cord, larynx, lungs, vertebrae, sternum, and intestine. Hoxa2 mRNA is a target of microRNA miR-3960 in differentiating mouse osteoblasts.
R-HSA-5617484 (Reactome) As inferred from mouse embryos, HOXA2 expression is directly driven by EGR2 (KROX20) in rhombomeres 3 and 5 (r3, r5) of the hindbrain and by HOXB1 in r4. EGR2 binds sites in the 5' region of the HOXA2 gene. HOXB1 sets up the correct EGR2 expression domain in r3 and thereby indirectly regulates HOXA2 in this region. (HOXA2 is the only HOX gene active in r2. An unknown activator, possibly a transcription factor of the SOX family, may be involved in expression in r2.)
R-HSA-5617485 (Reactome) The HOXB2 mRNA is translated to yield HOXB2 protein (Sengupta et al. 1994, Segara et al. 2005, Zhai et al. 2005).
R-HSA-5617486 (Reactome) The HOXB2 gene is transcribed to yield mRNA (in embryos in Giampaolo et al. 1989, in carcinoma cells in Simeone et al. 1990). In mouse embryos Hoxb2 mRNA is observed in rhombomere 3 and caudally in the neural tube and mesoderm derivatives such as lung.
R-HSA-5617492 (Reactome) As inferrred from mouse embryos, EGR2 (KROX20) binds three sites in the 5' region of the HOXB2 gene and activates expression in rhombomere 3 (r3) and r5. HOXB1 activates HOXB2 in r4 and expression is also observed in r6 and r7.
R-HSA-5617641 (Reactome) As inferred from mouse embryos, the transcription factor MAFB (KREISLER, KMRL) initially activates the HOXA3 gene in rhombomere 5 (r5) and r6. Weaker expression is also observed in r7. HOXA3 autoregulates by binding and activating its own promoter.
R-HSA-5617642 (Reactome) The HOXD3 gene is transcribed to yield mRNA (Zha et al. 2012). In mouse embryos Hoxd3 mRNA is observed in the neural tube with an anterior boundary at the junction of rhombomeres 4-5 and in the dorsal root ganglia, first cervical vertebra, thyroid gland, kidney tubules, esophagus, stomach, and intestines.
R-HSA-5617643 (Reactome) HOXA3 mRNA is translated to yield HOXA3 protein.
R-HSA-5617650 (Reactome) Retinoic acid induces expression of HOXD3 in neuroblastoma cells (Zha et al. 2012) and mouse embryos but it is unknown if the effect is direct or indirect. In mouse embryos the retinoid receptor Rarb is not responsible for the inducibility. As inferred from mouse embryos HOXD3 is expressed in rhombomeres 5, 6, and 7 (r5-7). As inferred from mouse Hoxd3, activation of HOXD3 chromatin is associated with loss of methylation at lysine-27 of histone H3 (H3K27), loss of PRC2, and gain of methylation at H3K4.
R-HSA-5617652 (Reactome) HOXD3 mRNA is translated to yield HOXD3 protein (Zha et al. 2012).
R-HSA-5617661 (Reactome) As inferred from mouse embryos, the MAFB:JUN (KREISLER:JUN) heterodimer binds the rhombomere 5 (r5) enhancer located 5' to the P1 promoter of the HOXB3 gene and activates expression in r5. EGR2 (KROX20) also binds the r5 enhancer is required to activate the HOXB3 gene in r5. After initial activation HOXB3 is hypothesized to maintain its own expression. HOXB3 is expressed most strongly in r5 and more weakly in caudal rhombomeres r6 and r7.
R-HSA-5617668 (Reactome) HOXB3 mRNA is translated to yield HOXB3 protein (Palakurthy et al. 2009, Li et al. 2012, Chen et al. 2013). Translation is repressed by the microRNAs miR-7 and miR-218 (Li et al. 2012) and miR-10A (Weiss et al. 2009).
R-HSA-5617672 (Reactome) The HOXB3 gene is transcribed to yield mRNA (in embryos in Giampaolo et al. 1989, in carcinoma cells in Simeone et al. 1990). The HOXB3 mRNA is a target of the microRNAs miR-7 and miR-218 in breast cancer cells (Li et al. 2012) and miR-10A (Weiss et al. 2009). In mouse embryos Hoxb3 mRNA is observed strongly in rhombomere 5 and more weakly in rhombomeres 6 and 7 of the hindbrain. Hoxb3 mRNA is also observed in mesodermal derivatives including lung, stomach, pancreas, and metanephros, and in neural crest derivatives.
R-HSA-5617676 (Reactome) The HOXA3 gene is transcribed to yield mRNA (Han et al. 2007). In mouse embryos Hoxa3 mRNA is observed in rhombomere 5 and caudally through the central nervous system, ectoderm, and somitic mesoderm. HOXA3 mRNA is a target of the microRNA miR-10a (Han et al. 2007).
R-HSA-5617855 (Reactome) HOXC4 mRNA is translated to yield HOXC4 protein.
R-HSA-5617859 (Reactome) As inferred from mouse embryos, retinoic acid activates the HOXB4 gene in rhombomere 7 (r7) by binding retinoic acid receptor RARB (Folberg et al. 1999) and perhaps RARA in RAR:RXR dimers bound to retinoic acid response elements (RAREs) located in the 3' flanking region of the HOXB4 gene, causing dissociation of corepressors and recruitment of coactivators. HOXB4 maintains its own expression by binding and activating its own promoter.
In human fibroblasts activation of chromatin at the HOXB4 gene accompanied by loss of methylation of lysine-27 at histone H3 (H3K27me3, Lan et al. 2007). Based on observations from mouse embryonic stem cells, Polycomb repressive complex 2 (PRC2), which binds H3K27me3, is anticipated to be lost while methylation of H3K4 is gained, possibly through the action of the histone demethylase KDM6A (UTX) which, in human fibroblasts, binds HOXB4 (Lan et al. 2007). Other factors may be involved in demethylating H3K27me3. KDM6A can form complexes containing the histone methyltransferases KMT2C,D (MLL2,3) which may participate in methylating H3K4 (Lee et al. 2007).
R-HSA-5617862 (Reactome) As inferred from mouse embryos, retinoic acid initially activates expression of the HOXA4 gene in rhombomere 7 (r7) by binding RARB or RARA in dimeric RAR:RXR complexes located at retinoic acid response elements (RAREs) in the 5' flanking region of the HOXA4 promoter (also observed in human teratocarcinoma cells in Doerksen et al. 1996, Sessa et al. 2007), correlating dissociation of corepressors and recruitment of coactivators. In mouse embryos Hoxa4 itself maintains later expression in an autoregulatory loop.
In human fibroblasts (Lan et al. 2007) and teratocarcinoma cells (Sessa et al 2007) activation of HOXA4 chromatin is accompanied by loss of methylation at lysine-27 of histone H3 (H3K27me3) and gain of H3K4me3. The polycomb repressive complex 2 (PRC2), which binds H3K27me3, is also reduced at active HOXA4 chromatin (Lan et al. 2007, Sessa et al. 2007).
R-HSA-5617864 (Reactome) HOXD4 mRNA is translated to yield HOXD4 protein (Zappavigna et al. 1991).
R-HSA-5617866 (Reactome) The HOXC4 gene is transcribed to yield mRNA. In mouse embryos Hoxc4 mRNA is observed caudal to rhombomere 7 in spinal column, prevertebrae, esophagus, metanephric kidney, lung, and trachea.
R-HSA-5617867 (Reactome) The HOXB4 gene is transcribed to yield mRNA (in embryos in Giampaolo et al. 1989, in carcinoma cells in Simeone et al. 1990). The microRNA miR-23a binds the 3' untranslated region of HOXB4 mRNA (Koller et al 2013). In mouse embryos Hoxb4 mRNA is observed in rhombomere 7, paraxial mesoderm of somite 7, and caudally.
R-HSA-5617874 (Reactome) The HOXD4 gene is transcribed to yield mRNA (Moroni et al. 1993, Morrison et al. 1996, Morrison et al. 1997). In mouse embryos Hoxd4 mRNA is observed in rhombomere 7 and caudally in spinal cord and prevertebrae. The HOXD4 promoter region is a target of the microRNA miR-10a, which causes repression of transcription (Tan et al. 2009).
R-HSA-5617877 (Reactome) The HOXA4 gene is transcribed to yield mRNA (Doerksen et al. 1996). In mouse cells, microRNAs miR-196a-2, miR-196b, and miRNA miR-222 target Hoxa4 mRNA untranslated regions. In mouse embryos Hoxa4 mRNA is observed in rhombomere 7, mesoderm (including somites, lung, and kidney), rostral-dorsal stomach, rostral prececal gut, and large intestine.
R-HSA-5617879 (Reactome) The HOXA4 mRNA is translated to yield HOXA4 protein. In mouse cells the microRNAs miR-196a-2, miR-196b, and miR-222 repress expression of Hoxa4.
R-HSA-5617881 (Reactome) HOXB4 mRNA is translated to yield HOXB4 protein. Protein expression is repressed by miR-23a (Koller et al. 2013).
R-HSA-5617887 (Reactome) As inferred from mouse embryos, HOXC4 is expressed at E12.5 caudal to rhombomere 7 (r7) and at the level of prevertebrae 4-5 and caudally. In carcinoma cells treated with retinoic acid (Lee et al. 2007) and primary fibroblasts (Lan et al. 2007) chromatin at HOXC4 loses methylation at lysine-27 of histone H3 (H3K27me3), loses polycomb repressive complex 2 (PRC2), and gains methylation at lysine-4 of histone H3 (H3K4me3). In embryonal carcinoma cells KDM6A (UTX) binds HOXC4 and participates in demethylating H3K27 at HOXC4 (Lee et al. 2007)
R-HSA-5617896 (Reactome) As inferred from mouse embryos, retinoic acid activates the HOXD4 gene in rhombomere 7 (r7) by binding RARB or RARA in RAR:RXR receptor dimers bound to a retinoic acid response element (RAREs) in the 5' flanking region of the gene. Ligand binding by retinoic acid receptors causes dismissal of corepressors such as NCOR1 and recruitment of coactivators such as NCOA3 (Klein et al. 2000). The response of HOXD4 to retinoic acid is also observed in human embryonal carcinoma cells (Moroni et al. 1993, Morrison et al. 1996, Morrison et al. 1997). PAX6 binds near the RARE and is required for maximal activation.
In human fibroblasts chromatin at HOXA genes is activated by loss of methylation at lysine-27 (H3K27me3), loss of Polycomb repressive complex 2 (PRC2), and gain of H3K4me3 (Lan et al. 2007). Similar changes occur at Hoxd4 in mouse embryos. The histone demethylase KDM6A (UTX) binds the HOXD4 gene in human lung fibroblasts and may participate in demethylating H3K27me3 (Lan et al. 2007). Other factors may also be involved in demethylation. KDM6A associates with the histone methyltransferases KMT2C,D (MLL2,3) which may participate in methylating H3K4 (Lee et al. 2007). As inferred from mouse homologs, PCGF2 (MEL18) dissociates from Hoxd4 during activation. After activation by retinoic acid, HOXD4 maintains its own expression by binding and activating its own promoter.
R-HSA-5621002 (Reactome) As inferred from mouse embryos, HOXB1 in a trimeric complex with PBX1 and MEIS1 or PKNOX1 (PREP1) binds an enhancer located 5' to the HOXB2 gene and activates expression of HOXB2 in rhombomere 4 (r4). EGR2 (KROX20) activates HOXB2 in r3 and r5 and expression is also observed in r6 and r7.
R-HSA-5621010 (Reactome) As inferred from mouse homologs, HOXA2 expression is driven by HOXB1 in rhombomere 4 (r4) and EGR2 (KROX20) in r3 and r5. HOXB1 together with PBX and PREP/MEIS cofactors bind an element in the intron of HOXA2. (HOXA2 is the only HOX gene active in r2. An unknown activator, possibly a transcription factor of the SOX family, may be involved in expression in r2.)
R-HSA-5693644 (Reactome) As inferred from mouse embryos and embryonal carcinoma cells, HOXB1 binds with the PBX1:PKNOX1 (PBX1:PREP1) heterodimer (Berthelsen et al. 1998) and MEIS1at the promoter of the HOXB1 gene to maintain expression after initial activation of HOXB1 by retinoic acid signaling. Binding of SOX:OCT heterodimers to the mouse HOXB1 promoter also appear to positively regulate HOXB1 transcription.
R-HSA-6810139 (Reactome) In human cell lines and tissues activation of HOXA2 chromatin by retinoic acid occurs through loss of methylation at lysine-27 of histone H3 (H3K27), dissociation of polycomb repressive complexes, and gain of methylation at H3K4 (Lee et al. 2007 Supplementary, Sakamoto et al. 2007, Sessa et al. 2007). The change in chromatin may be produced by euchromatin spreading from distant 3' retinoic acid response elements. DNA methylation and MBD1 also appear to play a role in maintaining repression at HOXA2 in HeLa cells (Sakamoto et al. 2007). The histone demethylase KDM6A binds HOXA2 (Lee et al. 2007 Supplementary) and may participate in removing H3K27 methylation. KDM6A associates with histone methyltransferases KMT2C,D (MLL2,3) which may participate in methylating H3K4 in embryonal carcinoma cells (Lee et al. 2007, also observed at other HOXA genes in Lan et al. 2007). The conformation of the entire HOXA cluster in the nucleus changes during differentiation of a myeloid leukemia cell line and the conformation changes correlate with gene activity, H3K27me2,3 occurence, and proximity to CTCF binding sites (Rousseau et al. 2014, see also Lonfat and Duboule 2015).
R-HSA-6810158 (Reactome) During activation of HOXB3 by retimoic acid in fibroblasts (Lan et al. 2007) and embryonal carcinoma cells (Lee et al. 2007) chromatin at HOXB3 loses methylation at lysine-27 of histone H3 (H3K27me3), loses PRC2, and gains methylation at H3K4. The demethylase KDM6A (UTX) binds HOXB3 chromatin during activation (Lan et al. 2007, Lee et al. 2007) and may participate in demethylating H3K27me3. KDM6A forms complexes with the histone methyltransferases KMT2C,D (MLL2,3) which may participate in methylating H3K4 (Lee et al. 2007)
R-HSA-6810159 (Reactome) During activation of HOXB1 by retinoic acid in human embryonal carcinoma cells, methylation at lysine-27 of histone H3 (H3K27me3) is lost and methylation at lysine-4 (H3K4me3) is gained (Lan et al. 2007, Lee et al. 2007). The histone demethylase KDM6A (UTX) binds HOXB2 chromatin and may demethylate H3K27me3 (Lee et al. 2007). Other factors may also participate in demethylation. Loss of H3K27me3 is associated with loss of polycomb repressive complex 2 (PRC2) (Lan et al. 2007, Lee et al. 2007). KDM6A forms complexes with the histone methyltransferases KMT2C,D (MLL2,3) which may participate in methylating H3K4 (Lee et al. 2007). The activation of HOXB1 chromatin may be produced by euchromatin spreading from distant 3' retinoic acid response elements.
R-HSA-6810161 (Reactome) In human fibroblasts (Lan et al. 2007) and human embryonic carcinoma cells (Lee et al. 2007, Sessa et al. 2007) treated with retinoic acid HOXA3 chromatin is activated by loss of methylation at lysine-27 of histone H3 (H3K27me3) and gain of H3K4me3. KDM6A (UTX) binds near HOXA3 (Lan et al. 2007, Lee et al. 2007) but does not appear to participate in the loss of H3K27me3. KDM6A forms complexes with the histone methyltransferases KMT2C,D (MLL2,3) which may participate in methylating H3K4 (Lee et al. 2007). Polycomb repressive complex 2 (PRC2), which binds H3K27me3, is also lost during activation of HOXA3 (Lan et al. 2007, Lee et al. 2007, Sessa et al. 2007). The change in chromatin at HOXA3 may result from euchromatin spreading from distant 3' retinoic acid response elements. The chromosomal conformation of the entire HOXA cluster changes during activation (Rousseau et al. 2014).
RARA,B:RXRA at HOXA4 bivalent chromatinR-HSA-5617862 (Reactome)
RARA,B:RXRA at HOXB4 bivalent chromatinR-HSA-5617859 (Reactome)
RARA,B:RXRA at HOXD4 bivalent chromatinR-HSA-5617896 (Reactome)
RARA,G:RXRA at HOXA1 bivalent chromatinR-HSA-5617431 (Reactome)
RARA,G:RXRA at HOXB1 bivalent chromatinR-HSA-5617452 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617431 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617445 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617452 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617484 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617492 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617641 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617650 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617859 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617862 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617887 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5617896 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5621002 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
R-HSA-5621010 (Reactome)
RQCD1ArrowR-HSA-5617471 (Reactome)
atRA:RARA,B:RXRA at

active HOXA4

chromatin
ArrowR-HSA-5617862 (Reactome)
atRA:RARA,B:RXRA at

active HOXA4

chromatin
ArrowR-HSA-5617877 (Reactome)
atRA:RARA,B:RXRA at

active HOXB4

chromatin
ArrowR-HSA-5617859 (Reactome)
atRA:RARA,B:RXRA at

active HOXB4

chromatin
ArrowR-HSA-5617867 (Reactome)
atRA:RARA,B:RXRA at

active HOXD4

chromatin
ArrowR-HSA-5617874 (Reactome)
atRA:RARA,B:RXRA at

active HOXD4

chromatin
ArrowR-HSA-5617896 (Reactome)
atRA:RARA,G:RXRA at

active HOXA1

chromatin
ArrowR-HSA-5617431 (Reactome)
atRA:RARA,G:RXRA at

active HOXA1

chromatin
ArrowR-HSA-5617471 (Reactome)
atRA:RARA,G:RXRA at

active HOXB1

chromatin
ArrowR-HSA-5617452 (Reactome)
atRA:RARA,G:RXRA at

active HOXB1

chromatin
ArrowR-HSA-5617454 (Reactome)
atRA:RARA,G:RXRA at

active HOXB1

chromatin
R-HSA-5693644 (Reactome)
atRAArrowR-HSA-5617445 (Reactome)
atRAArrowR-HSA-5617650 (Reactome)
atRAArrowR-HSA-6810139 (Reactome)
atRAArrowR-HSA-6810159 (Reactome)
atRAR-HSA-5617431 (Reactome)
atRAR-HSA-5617452 (Reactome)
atRAR-HSA-5617859 (Reactome)
atRAR-HSA-5617862 (Reactome)
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