期刊
GENES & DEVELOPMENT
卷 26, 期 24, 页码 2749-2762出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.203356.112
关键词
epigenetics; HOX genes; histone modification; neuronal differentiation; PHD domains; PRMT7
资金
- NIH [R01 GM095659, R01 CA157919, CCSG 5 P30 CA0166672 35, GM064844, R37GM037120]
- Cancer Prevention and Research Institute of Texas [RP110183]
- Center for Cancer Epigenetics at M.D. Anderson Cancer Center
- Deutsche Akademie der Naturforscher Leopoldina [LPDS 2009-5]
- Empire State Training Program in Stem Cell Research (NYSTEM) [C026880]
- Howard Hughes Medical Institute
Mixed-lineage leukemia 4 (MLL4; also called MLL2 and ALR) enzymatically generates trimethylated histone H3 Lys 4 (H3K4me3), a hallmark of gene activation. However, how MLL4-deposited H3K4me3 interplays with other histone marks in epigenetic processes remains largely unknown. Here, we show that MLL4 plays an essential role in differentiating NT2/D1 stem cells by activating differentiation-specific genes. A tandem plant homeodomain (PHD4-6) of MLL4 recognizes unmethylated or asymmetrically dimethylated histone H4 Arg 3 (H4R3me0 or H4R3me2a) and is required for MLL4's nucleosomal methyltransferase activity and MLL4-mediated differentiation. Kabuki syndrome mutations in PHD4-6 reduce PHD4-6's binding ability and MLL4's catalytic activity. PHD4-6's binding strength is inhibited by H4R3 symmetric dimethylation (H4R3me2s), a gene-repressive mark. The protein arginine methyltransferase 7 (PRMT7), but not PRMT5, represses MLL4 target genes by up-regulating H4R3me2s levels and antagonizes MLL4-mediated differentiation. Consistently, PRMT7 knockdown increases MLL4-catalyzed H3K4me3 levels. During differentiation, decreased H4R3me2s levels are associated with increased H3K4me3 levels at a cohort of genes, including many HOXA and HOXB genes. These findings indicate that the trans-tail inhibition of MLL4-generated H3K4me3 by PRMT7-regulated H4R3me2s may result from H4R3me2s's interference with PHD4-6's binding activity and is a novel epigenetic mechanism that underlies opposing effects of MLL4 and PRMT7 on cellular differentiation.
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