title: Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4.
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 (PHD(4-6)) 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 PHD(4-6) reduce PHD(4-6)'s binding ability and MLL4's catalytic activity. PHD(4-6)'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 PHD(4-6)'s binding activity and is a novel epigenetic mechanism that underlies opposing effects of MLL4 and PRMT7 on cellular differentiation.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Dhar
authors.forename: Sung-Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Pu-Yeh
authors.initials: PY
authors.lastname: Kan
authors.forename: Philipp
authors.initials: P
authors.lastname: Voigt
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
authors.forename: Danny
authors.initials: D
authors.lastname: Reinberg
authors.forename: Min Gyu
authors.initials: MG
authors.lastname: Lee
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008745:Methylation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000166:cytology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics; D013234:Stem Cells / Q000166:cytology
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; C088144:HoxA protein; C487994:PRMT7 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human