Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4 (original) (raw)

  1. Sung-Hun Lee1,5,
  2. Pu-Yeh Kan1,
  3. Philipp Voigt2,
  4. Li Ma1,
  5. Xiaobing Shi3,
  6. Danny Reinberg2 and
  7. Min Gyu Lee1,4,6
  8. 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  9. 2Howard Hughes Medical Institute, Department of Biochemistry, New York Univeristy School of Medicine, New York, New York 10016, USA;
  10. 3Department of Biochemisty and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  11. 4Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
  12. ↵5 These authors contributed equally to this work.

Abstract

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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