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

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1, 6, 7, 9, 19...5393410, 20, 28, 4125, 29, 5250, 5423, 43, 502550, 5414, 29, 50, 54, 6710, 20, 23, 41, 50...12, 15, 33, 573, 8, 17, 38, 44...4, 16, 5550, 5415, 29, 33, 5223532329, 52238, 50, 51, 54, 5811, 22, 51, 54, 5850, 5415, 654018, 32, 50, 51, 54...23, 433, 38, 59, 6229, 36, 528, 39, 50, 51, 58nucleoplasmcytosolHIST1H2BN HIST1H2AC RARA POLR2A HIST1H4 HIST1H2AC HIST2H2AA3 H2AFZ HIST1H2AD H2AFV HIST1H2AC H2AFX HIST1H2BH POLR2B Me3K5-HIST2H3A Me3K-28-H3F3A HIST2H2AA3 H2AFV HIST2H2AC POLR2H HIST1H2BJ HIST1H2BC H2AFV H2AFV POLR2J POLR2C H2AFX HIST1H2BN HIST1H2AD PKNOX1 HIST3H2BB POLR2K HIST1H2BD HIST1H2BN POLR2B HIST1H2BM POLR2J HIST1H2BN HIST1H2AJ HIST1H2BB HIST1H2BH EED HIST1H2BD KDM6A Me3K-28-HIST1H3A HIST1H2BN EED HIST1H2AB H2AFJ HIST1H2BL Me3K5-HIST2H3A PAXIP1 KMT2C HIST1H2BO H2BFS HOXB1:PBX1:PKNOX1and MEIS1 at activeHOXB1 chromatinPOLR2F HIST1H2AD SUZ12 HIST2H2AC HIST1H2BL HIST2H2BE HIST1H2BC H2AFX HIST2H2AA3 HIST1H2BD HIST1H2BL PAGR1 SUZ12 Me3K-28-HIST1H3A H2AFB1 HIST1H2BB HIST1H2BC POLR2K HIST1H2BJ HIST1H2AD Me3K5-HIST2H3A SUZ12 HIST1H2BN H2BFS HIST1H2BC POLR2G HOXA4 mRNAKMT2C HIST2H2BE MAFB HIST1H2BM H2AFB1 HIST1H2AB H2BFS EZH2 POLR2E HIST1H2BD HIST1H4 H2BFS EED H2AFX HIST1H2BA WDR5 PAGR1 PAGR1 HIST3H2BB H2AFV HIST2H2AA3 H2BFS POLR2F WDR5 atRA HIST2H2AA3 POLR2F POLR2A Me3K5-HIST2H3A KMT2D HIST3H2BB POLR2K HIST2H2AC HIST1H2BD H2BFS H2BFS HIST1H4 POLR2D HIST1H2BM Me3K5-HIST2H3A HIST1H2BA HIST1H2BB Me3K-28-HIST1H3A HOXD1POLR2G HOXB3 gene HIST1H2BK POLR2L HIST1H2BA HIST2H2BE HIST1H2BK HIST1H2BN EP300 H2AFJ H2AFZ H2AFX RBBP5 HIST1H4 H2AFX HIST1H2AD RXRA HIST3H2BB Me3K5-HIST1H3A RBBP4 POLR2B NCOA6 H2AFX Me3K-28-H3F3A HIST1H4 H2AFZ HIST1H2BH KMT2C HIST1H2BA Me3K-28-HIST2H3A HOXA4 gene KMT2C PAGR1 HIST1H2AJ HIST1H2BB HIST1H2BO POLR2F HIST1H2BM HOXD1 gene H2AFJ KDM6A HIST1H2AD H2AFV POLR2K HIST1H2AC H2AFB1 H2AFB1 PAXIP1 HIST1H2BM NCOA6 EZH2 EGR2HIST1H2BK NCOR1 HIST1H2BJ POLR2K HIST1H2BK HIST1H2BB Me3K5-H3F3A EGR2 H2AFJ H2AFZ HOXD1 geneHIST3H2BB ASH2L Me3K5-H3F3A HIST1H2BK RARG HIST1H2BO Me3K-28-HIST2H3A H2AFJ H2AFX HIST1H2AJ Me3K5-HIST2H3A H2AFZ KDM6A Me3K5-HIST2H3A KMT2D HIST1H2AB HIST2H2AA3 HIST2H2AC POLR2C HIST3H2BB H2AFZ HIST1H2BA HIST1H2BL HIST1H4 Me3K-28-HIST1H3A RBBP4 POLR2L H2AFZ HIST1H2BD HIST1H2AC HIST1H2BH EP300 NCOR1Me3K5-HIST1H3A HIST1H2BL NCOA6 HIST1H2BJ HIST2H2BE HIST1H2BC HOXA1 gene HIST1H2BA Me3K5-HIST1H3A POLR2I POLR2B Me3K5-H3F3A H2AFX H2AFV HIST1H2BK HIST1H2BM H2AFZ POLR2J H2AFJ Me3K5-H3F3A HIST1H2AC H2AFX ASH2L HIST1H2AC HIST1H2AD HIST3H2BB EED H2AFV PBX1 Me3K5-HIST2H3A POLR2D CTCF HIST2H2BE HIST1H2BJ HOXB1 gene Me3K5-HIST1H3A Me3K5-HIST2H3A Me3K-28-HIST2H3A HIST1H2BD Me3K5-HIST1H3A POLR2H Me3K5-HIST2H3A Me3K5-H3F3A HIST1H2BH POLR2K HIST2H2BE H2AFZ HIST3H2BB EED HIST1H2AD HIST1H2BN HIST1H2BB atRA HOXD1 bivalentchromatinASH2L HIST1H2AB HOXB4 gene Me3K5-HIST1H3A ASH2L H2AFV H2AFJ Me3K5-HIST1H3A HIST1H4 HIST1H2BH POLR2E HIST1H2BB POLR2K HIST1H2BJ ASH2L POLR2J HIST1H2BJ RBBP5 Me3K5-H3F3A Me3K5-H3F3A HIST1H2BL POLR2F PAGR1 H2AFZ RBBP5 HIST1H4 POLR2F POLR2I HIST1H2BN PCGF2 EZH2 POLR2L Me3K5-HIST2H3A H2AFX HIST1H2BN POLR2J HOXB1:PBX1:PKNOX1 atactive HOXA2chromatinPBX1 HDAC3HIST1H2BK HIST1H4 HOXB2 gene Me3K5-HIST1H3A HIST2H2AA3 HIST1H2BB HIST1H2BA HIST1H2AB HIST1H2BN RBBP4 HIST1H2AC HIST1H2BD KMT2D POLR2L PKNOX1 HIST1H2BO HIST2H2AC HIST1H2BC HIST1H2BH POLR2J Me3K5-H3F3A atRA HIST2H2AA3 KMT2D HIST1H4 HIST3H2BB HIST1H2BC HIST1H2BK RBBP5 POLR2L Me3K-28-HIST1H3A HIST2H2AC HIST1H2BB HIST1H4 HIST2H2AA3 POLR2J HIST1H2BM HIST2H2BE HOXA2 gene Me3K-28-HIST2H3A H2AFZ POLR2L HIST1H2BC HIST1H2BD HIST1H2BM HOXB1 geneHIST3H2BB HIST1H2BO EZH2 HIST1H2AJ Me3K-28-HIST2H3A POLR2L HIST1H2BN HIST1H2AJ POLR2E PAXIP1 HIST1H2AC Me3K5-HIST2H3A HIST2H2AC HIST1H2BH RBBP7 RBBP4 HIST2H2BE HIST1H2BN POLR2D H2AFV POLR2B HIST1H2AJ POLR2H HIST2H2AA3 Me3K5-H3F3A HIST2H2AA3 HIST2H2AC PBX1:PKNOX1HIST1H2BH WDR5 HIST1H2AC HIST1H2AJ HIST1H2BK HIST1H2AC Me3K5-H3F3A Me3K5-HIST1H3A HIST2H2BE HIST1H2AB HOXD4 mRNAH2AFB1 HIST1H2AD H2AFJ NCOA3HIST1H2BL HOXB3 bivalentchromatinHIST1H2AC POLR2A HIST1H2BD H2AFX EZH2 HIST1H2BB H2AFX PRC2 (EZH2) CoreHOXB2 activechromatinEED HIST1H2BK H2AFB1 Me3K5-HIST1H3A HIST1H2BN HIST1H4 HIST1H2BL H2AFV H2AFX HOXA4HIST1H2BM POLR2I HIST1H2BH HIST1H2BK H2AFB1 Me3K5-HIST1H3A HOXA1 gene HOXB1 gene PCGF2WDR5 EZH2 HOXA4 gene HOXD3 bivalentchromatinHOXA3 activechromatinHIST1H2AD HIST1H2BJ HIST2H2BE ASH2L HIST1H2BM PAGR1 HIST1H2BN atRA:RARA,G:RXRA atactive HOXA1chromatinMe3K5-H3F3A HOXD4HIST1H2BH HIST1H2BA ASH2L NCOR1 RBBP5 HIST1H2BA H2AFV HIST2H2AC WDR5 HIST1H2BC EED Me3K-28-H3F3A H2BFS EGR2 at active HOXA2chromatinMLL2,3 complexSUZ12 HIST2H2AC EP300 H2AFB1 H2BFS POLR2D HIST3H2BB H2BFS HIST1H2BH H2AFX POLR2L SUZ12 HIST1H2BB HIST1H2BL POLR2D KMT2C AJUBAH2AFZ HOXA3 bivalentchromatinHOXA2 mRNAMe3K5-HIST1H3A HIST1H2BC KMT2D HIST1H2BK HIST1H2BO WDR5 HIST1H2BC RBBP7 Me3K5-H3F3A ASH2L PAGR1 HIST1H2BL H2AFZ H2AFB1 RXRA HIST1H2BO Me3K5-H3F3A HIST1H2BL HOXC4 bivalentchromatinH2AFV POLR2G HIST1H2BO HIST1H2BJ PAXIP1 POLR2K HOXD1 gene Me3K-28-HIST1H3A HIST1H2BA HIST1H2BC H2BFS HIST1H2BD EZH2 HIST1H2BA POLR2I H2AFB1 Me3K5-H3F3A POLR2J POLR2E Me3K5-H3F3A HIST1H2BH HIST1H2AB SUZ12 Me3K5-H3F3A POLR2C HIST1H2AD HIST1H2BL POLR2I Me3K5-HIST1H3A HIST1H2BO HIST1H2AJ POLR2E HIST1H2BJ HIST1H2BC RBBP7 HIST1H2AD HIST1H2BK CNOT6:ZNF335H2AFZ HIST1H2BJ POLR2G H2AFJ HIST2H2AC HIST3H2BB HIST1H2BH HIST1H2AJ KMT2C H2BFS PBX1 Me3K-28-HIST2H3A HIST1H4 PBX1 EP300 POLR2B RBBP4 HIST1H2BM HIST1H2BJ H2AFV HOXB4 geneHOXD4 geneMe3K-28-HIST1H3A H2AFX MEIS1 SUZ12 HOXB2 geneHIST1H2BM H2AFJ HOXA1 mRNAMe3K5-HIST1H3A KDM6A RBBP5 HIST1H2BL HIST1H2BM RBBP7 HIST1H2BN HIST3H2BB H2AFV PAGR1 HIST1H2BH H2AFZ HIST1H2BC POLR2E POLR2C HIST1H2BN NCOA6 KMT2C HIST1H2BO KDM6A HIST1H2BB HIST1H2BL HIST1H2BH PAXIP1 EZH2 H2AFV HOXD3 mRNAPOLR2A POLR2H PBX1 H2BFS POLR2L Me3K5-HIST2H3A HIST1H4 H2BFS H2AFJ H2AFV EGR2JUN WDR5 HIST1H2BH HIST1H2BM HIST1H2AJ H2AFB1 KMT2D H2AFJ KDM6A H2AFB1 Me3K5-HIST2H3A POLR2I HIST1H4 POLR2B HIST1H2BC HIST2H2AA3 POLR2K HIST1H2AD HOXB3 geneHIST1H2BD EZH2 HIST2H2AA3 HIST1H2BL HIST1H2AJ HOXA4 geneHIST2H2AC Me3K-28-H3F3A HIST1H2BA Me3K5-HIST1H3A atRA:RARA,B:RXRA atactive HOXA4chromatinHOXB3 mRNAHOXA3 mRNAatRA HIST3H2BB HOXD3POLR2B HIST1H2BM HIST1H2BD HIST1H2BN HIST1H2BN HIST2H2AC POLR2C HIST1H2BB NCOA6 KDM6A Me3K-28-HIST1H3A HIST1H2AB HIST1H2BA PKNOX1 HIST1H2BJ atRA:RARA,B:RXRA atactive HOXD4chromatinPOLR2I POLR2J HIST1H2BK HIST1H2BA HIST1H2AC NCOA3 CREBBPHIST1H2BN Me3K-28-H3F3A Me3K-28-H3F3A HIST1H2BB HIST1H2BB POLR2C H2BFS HOXC4 mRNAPOLR2L HIST1H2AJ HIST3H2BB HIST2H2BE Me3K5-HIST2H3A HIST1H2BO Me3K-28-H3F3A POLR2B NCOR1 POLR2E POLR2G POLR2L WDR5 HIST1H2BA HIST1H2BO H2AFV RBBP5 HIST1H2AD HIST1H2BH HIST1H2BH HIST1H2AJ HIST1H2BJ EED HIST2H2AA3 HIST1H2BO HIST1H2BD HIST2H2AC HIST1H2BB HIST1H2BD HIST1H2BL HIST1H2BM HIST1H2BH H2AFX H2AFB1 HOXB1:PBX1:MEIS1,PKNOX1 at active HOXB2 chromatinHIST1H2BA H2AFX HIST1H2BC POLR2G POLR2J HOXB1 POLR2I Me3K5-H3F3A HOXA3H2AFB1 HIST2H2AC HIST3H2BB PBX1 HIST1H2BJ HIST1H2AC PAXIP1 RARA YY1 Me3K5-HIST2H3A HIST1H2BL HIST1H2BH POLR2G H2AFV PAXIP1 HOXD3 activechromatinMe3K5-H3F3A RXRA H2AFB1 HIST2H2BE POLR2F ASH2L HIST1H2BJ HIST1H4 HIST1H2BA HIST1H2AD EED H2BFS POLR2E HIST1H2AB Me3K5-HIST2H3A NCOA6 HIST2H2BE KMT2C HIST1H2BJ Me3K5-HIST1H3A HIST2H2AC HIST1H2AC HIST1H2AD RBBP5 RARB SUZ12 HOXA2 gene PAGR1 RXRA Me3K-28-HIST2H3A HIST1H2BA HIST2H2BE WDR5 HIST1H2AJ HDAC3 H2AFX H2AFZ HIST1H2BM H2BFS RBBP7 HIST1H2BH HIST1H2BB EGR2 HIST1H2BN HIST1H2BM HIST1H2BK RBBP5 HIST1H2AD AJUBA HIST1H2BJ HIST2H2AA3 KMT2D HIST1H2BD Me3K5-HIST2H3A RARB PKNOX1 HIST1H2BD HOXB1 HIST1H2BH HIST2H2AA3 Me3K5-HIST1H3A RARA POLR2J POLR2C HIST1H2BL PAGR1 HIST1H2BO RARG HIST1H2BL RBBP7 MAFB:JUN and EGR2 atactive HOXB3chromatinHIST1H2BL H2AFX NCOA3 HIST1H2BH HOXD1 mRNAMe3K5-H3F3A HIST1H2BN POLR2C HIST1H2BD HIST2H2BE POLR2A KMT2C H2AFB1 H2AFX HOXC4 activechromatinHIST1H2BC POLR2K POLR2G POLR2H Me3K5-HIST2H3A HIST1H2BD HIST1H2BA HIST1H2BJ H2AFJ POLR2C CTCF RBBP5 RNA Polymerase IIholoenzyme complex(generic)H2AFZ HIST2H2BE H2BFS POLR2I PAXIP1 RXRA HIST1H2BL KMT2C EGR2MEIS1 POLR2B Me3K-28-HIST2H3A HOXA3 gene HIST1H2BD Me3K-28-H3F3A HIST1H2BD POLR2F HIST1H2BO Me3K5-H3F3A HIST1H2AD HIST2H2AC atRA:RARA,G:RXRA atactive HOXB1chromatinHIST1H2BL HIST1H2BA H2AFZ RXRA HIST1H2BK HIST1H2AJ HIST1H2AJ HIST1H2BN HIST1H2BL PBX1 HIST1H2BD Me3K5-H3F3A HIST1H2BD Me3K5-HIST1H3A HIST1H2BM Me3K5-HIST2H3A HIST1H2BM PAX6HIST1H2BJ POLR2J KMT2D HIST3H2BB NCOA6 Me3K5-H3F3A H2AFJ HIST1H2AB RBBP5 POLR2H HIST1H2BB Me3K5-HIST1H3A HIST2H2AC HIST1H2AC KDM6A HIST1H2BA HIST1H2BB HIST2H2BE HIST1H2BN MAFBHOXA2 geneRARA H2AFJ HIST2H2AA3 HIST1H2AC HOXA3 gene Me3K5-HIST1H3A CREBBP POLR2K POLR2B POLR2D H2AFX Me3K-28-H3F3A HIST1H2BJ POLR2I HIST1H2BN HIST1H2BB MEIS1 HIST1H2BO HIST1H2AB HIST1H2BO HOXB2HIST1H2BM HOXA3 gene HIST1H2AC HIST1H2BC POLR2A Me3K5-HIST2H3A POLR2G NCOR1 HIST1H2AC NCOA6 RBBP7 H2AFJ Me3K-28-HIST2H3A H2AFJ POLR2G HIST1H2BM HOXA1HIST1H2BM HIST2H2AA3 Me3K5-HIST1H3A HIST1H2BH H2AFV H2BFS HIST1H2BA HIST1H2AB H2BFS Me3K5-HIST2H3A HIST1H2BC H2AFV HIST1H2AB Me3K5-H3F3A HIST1H2AJ ASH2L PAXIP1 RBBP4 HIST1H2BJ HIST1H4 POLR2B HIST1H2BL H2BFS Me3K5-H3F3A HIST1H2BL Me3K5-HIST1H3A HIST1H4 HIST1H2BK HIST1H2BC HIST1H2BM HIST1H2AJ SUZ12 HIST2H2AA3 Me3K5-HIST1H3A HIST1H2AD HIST1H2AB KMT2D POLR2C HIST2H2AA3 HOXC4 gene HOXB1 mRNAHIST1H2AJ HIST1H2BA HOXB3 gene POLR2A H2AFX Me3K-28-HIST1H3A HIST3H2BB HIST1H2BC PAXIP1 EP300 POLR2D HIST1H2BO KMT2C Me3K5-HIST2H3A HIST1H4 KMT2D HOXA3 genePOLR2I HIST2H2AC RXRA HOXC4 gene HIST1H4 HIST1H2BK H2AFB1 HIST1H2BD HIST1H2BH H2AFV EED POLR2K PKNOX1 H2AFJ HIST3H2BB EGR2 HIST1H4 PAXIP1 HIST1H2AB HIST1H2AB HIST2H2AA3 JUNPOLR2H HIST1H2BK POLR2K RBBP4 HIST2H2BE HIST1H2AJ RXRA ZNF335 HIST1H2AJ HIST2H2AC H2BFS HIST1H4 Me3K5-HIST2H3A RQCD1HIST1H2BJ KDM6A HOXC4 genePOLR2F HIST1H2BM EP300PAGR1 PKNOX1 ASH2L HIST2H2BE HIST1H2AB H2AFB1 HIST1H2BJ POLR2F RARB EGR2HIST1H2AC HOXB3 activechromatinHIST1H2AB HIST1H2BH H2AFX HIST1H2BB HIST1H2BO RBBP7 HIST1H2AB RARA POLR2I ASH2L HIST3H2BB PIAS2H2AFB1 KMT2C HIST3H2BB Me3K-28-HIST1H3A H2BFS HIST1H2BD POLR2I HIST2H2AC HOXB2 gene Me3K5-H3F3A Me3K5-H3F3A KMT2C HIST2H2AA3 Me3K-28-HIST1H3A HIST1H2BA HIST2H2BE RBBP4 HIST1H2BL KMT2C POLR2A HIST1H2BH HIST1H4 HIST1H2BK atRAHIST1H2BA HIST1H2BD HOXA2 gene Me3K5-HIST2H3A Me3K5-HIST1H3A H2AFX H2AFV HIST1H2BK Me3K5-HIST1H3A H2AFV HOXB1 gene POLR2K HIST1H2BA HIST2H2BE POLR2C WDR5 HIST1H2BO RARB RBBP5 HIST1H2BD PAGR1 KMT2C HIST1H2AJ HIST1H2AC HIST1H2BN H2AFJ HIST2H2AA3 H2BFS HIST1H2AB HIST1H4 POLR2G ASH2L HIST1H2BC RARA,G:RXRA at HOXB1bivalent chromatinCNOT6 POLR2G HIST1H2BK PAXIP1 HOXB3 gene EED Me3K-28-HIST1H3A SUZ12 HIST1H2BJ POLR2L HOXB1 POLR2G HIST1H2BC POLR2H HIST2H2AA3 RXRA PKNOX1 H2AFB1 HIST2H2AC Me3K5-HIST1H3A POLR2J HIST1H2AD H2AFJ H2AFJ NCOR1 HIST1H2BJ HIST1H2BD HIST1H2AD H2AFJ POLR2D PAXIP1 HIST1H2BK RARA,B:RXRA at HOXD4bivalent chromatinH2AFB1 HOXB4HIST2H2BE RARA POLR2B KDM6A HIST3H2BB HIST1H2AC YY1 H2AFZ H2AFZ H2BFS H2AFB1 atRA:RARA,B:RXRA atactive HOXB4chromatinHIST1H2AB HIST1H2BO H2AFB1 Me3K-28-H3F3A POLR2A KDM6A H2AFJ H2AFZ HIST1H2AC PAXIP1 POLR2J HIST1H2BK Me3K5-HIST1H3A H2BFS WDR5 RBBP4 HIST1H2AD POLR2L RBBP7 NCOA6 H2AFX HIST1H2AD RARA HIST1H4 Me3K5-H3F3A POLR2F POLR2F HIST1H2BN HIST1H2AJ POLR2D POLR2A ASH2L PAGR1 HIST2H2AA3 Me3K5-H3F3A WDR5 HIST1H2BC PAX6 HIST1H2BO POLR2G HOXB1 NCOA3 NCOA6 HIST2H2AA3 POLR2K Me3K5-H3F3A Me3K5-HIST2H3A H2AFJ HIST3H2BB HIST1H2BK HIST1H2BM HIST1H2BL HIST1H2BC H2AFV H2AFJ HIST1H2BD H2BFS H2AFZ HIST2H2AA3 Me3K5-H3F3A H2BFS HIST1H2AD NCOA6 HIST2H2AC HIST1H2AD Me3K5-HIST1H3A HIST1H4 POLR2B H2BFS POLR2D H2AFX HIST1H2BL H2AFJ Me3K-28-H3F3A H2AFB1 HIST1H2AC RARA HIST1H2BO HIST1H2BB Me3K5-H3F3A HIST1H2BD Me3K5-HIST2H3A KMT2D NCOA3 HIST1H2AC HIST1H2AD HIST1H4 HIST1H2BO HOXB2 bivalentchromatinPOLR2L H2BFS HOXB4 gene H2AFJ HIST1H2BA H2AFJ HIST1H2BJ RBBP7 PBX1 HIST1H2AJ HIST1H2AC POLR2E HIST1H2BL POLR2G H2AFZ POLR2E MEIS1HIST1H4 HIST1H2BO H2AFV HIST1H2BK PAGR1 HIST1H2AB HIST1H2AD NCOA3 HIST1H2BJ HIST1H2AB POLR2A H2AFZ PBX1:PKNOX1,MEIS1KMT2D HIST2H2BE H2AFV HIST2H2AA3 EZH2 H2AFB1 HIST2H2AC HIST3H2BB H2AFZ KDM6A HIST1H2BL POLR2H HIST1H2AC HOXB1H2AFV SUZ12 POLR2F POLR2D POLR2E PBX1:PKNOX1EZH2 HIST1H2AC H2AFX WDR5 POLR2H KMT2C POLR2E H2AFB1 HIST2H2AC KDM6A HOXA2 gene H2AFB1 RBBP7 H2AFZ HOXD4 gene POLR2H HIST1H2BA PAGR1 HIST1H2BK POLR2C RARA Me3K5-HIST2H3A HIST2H2BE NCOA6 POLR2H HIST1H2BB HIST1H4 POLR2D HOXC4KMT2D Me3K5-HIST1H3A HIST1H2AD HOXA2 bivalentchromatinRBBP4 H2AFB1 H2AFV EZH2 POLR2A POLR2D HIST1H2BJ POLR2H HIST2H2AC NCOA6 POLR2K H2AFJ POLR2E HIST1H2BN EGR2 at active HOXB2chromatinHIST1H2BM H2AFZ HIST1H2BA HIST2H2AA3 POLR2A HIST1H2BM HIST1H2BC HIST3H2BB PAXIP1 HIST1H2BK H2AFB1 Me3K-28-HIST2H3A WDR5 H2AFB1 HIST1H2BB NCOA6 CTCF HIST1H2BK HIST1H2BB RBBP4 POLR2F HIST1H2AB POLR2I HIST1H2AB KDM6A HIST1H4 RBBP5 HIST2H2AC MAFB,HOXB1:PBX1:PKNOX1at active HOXA3chromatinH2AFZ KDM6A HIST3H2BB POLR2J HIST2H2BE POLR2E HIST1H2BN HIST2H2BE POLR2A POLR2L HIST1H2AJ Me3K5-HIST1H3A RARG PAGR1 HIST2H2BE POLR2D HIST1H2AB HIST3H2BB HIST1H2BO H2AFV HIST1H2AC HOXB2 gene POLR2C RARB HIST1H2BC POLR2F HIST1H2BO HIST1H2BK POLR2H HIST1H2AD KMT2D HIST1H2AB CTCF HIST1H2AJ HIST1H2BH ASH2L HOXB2 gene RBBP7 RBBP5 RBBP5 HIST1H2BO POLR2E POLR2H Me3K5-HIST2H3A HOXD3 geneRARA,B:RXRA at HOXA4bivalent chromatinHIST1H2BC H2AFB1 HIST2H2AA3 NCOA6 HIST1H2BA POLR2D HIST1H2BC Me3K5-HIST2H3A HIST1H2BC ASH2L HIST1H2BC HOXA1 geneHOXB3HIST1H2BN atRA HOXD3 gene HIST3H2BB HIST1H2BO RBBP4 RARG HIST1H2AB POLR2J EZH2 POLR2D Me3K5-HIST1H3A HIST1H2BL POLR2I HIST1H2AB HOXA2 activechromatinWDR5 HOXD3 gene POLR2I HIST1H2BB HIST1H2AD POLR2A HIST2H2BE HIST1H2BN POLR2L POLR2A HIST1H2BO POLR2C HOXB2 mRNAHIST1H2AJ H2AFX POLR2E EED HIST1H2AC POLR2F HIST1H2AJ SUZ12 POLR2H Me3K-28-HIST2H3A KMT2D HIST1H2BM HIST1H2BM HIST1H2AC RARB Me3K-28-HIST2H3A HIST3H2BB POLR2C HIST2H2BE HIST1H4 HOXD1 activechromatinPOLR2G HIST1H2BB HIST1H2BD POLR2B SUZ12 HIST1H2BJ WDR5 HIST2H2BE RBBP4 HIST1H2BJ HIST1H2BB HIST1H2AB RARA,B:RXRA at HOXB4bivalent chromatinHIST3H2BB KDM6A RBBP5 H2AFX PKNOX1 HIST1H2BM HIST1H2BB HOXA2PAXIP1 H2AFJ H2AFZ HIST1H2AJ MAFB Me3K5-HIST2H3A HIST2H2AC H2AFZ HOXD4 gene H2AFJ HIST2H2AC RARA Me3K-28-H3F3A HIST1H2BA HIST1H2AJ NCOA6 H2AFZ HIST2H2AA3 RXRA HIST2H2AC H2BFS KMT2D HIST1H2BK HIST2H2BE HIST1H2BO HIST1H2AJ POLR2C RARA,G:RXRA at HOXA1bivalent chromatinPBX1:PKNOX1HIST1H2BH HIST1H2BB HIST1H2AD POLR2B H2AFX HIST1H2BB HIST2H2AC HOXB4 mRNARBBP7 HIST1H2BH HIST3H2BB HIST1H2AB H2AFV EED 840406650, 54, 674023, 43, 5050, 5450, 5411, 51, 5450, 548, 50, 51, 5450, 5450, 5410, 20, 23, 41, 50...50, 545410, 20, 23, 41, 50...50, 54232, 13, 26, 45, 4850, 5450, 5450, 5423, 43, 508, 50, 51, 5450, 54, 6711, 51, 5450, 54850, 548, 39, 50, 5123


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: 62
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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