Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4.

[kabuki syndrome]

Mixed -lineage leukemia 4 (MLL 4 ; also called MLL 2 and ALR ) enzymatically generates trimethylated histone H 3 Lys 4 (H 3 K 4 me 3 ), a hallmark of gene activation . However , how MLL 4 -deposited H 3 K 4 me 3 interplays with other histone marks in epigenetic processes remains largely unknown . Here , we show that MLL 4 plays an essential role in differentiating NT 2 /D 1 stem cells by activating differentiation-specific genes . A tandem plant homeodomain (PHD (4 -6 )) of MLL 4 recognizes unmethylated or asymmetrically dimethylated histone H 4 Arg 3 (H 4 R 3 me 0 or H 4 R 3 me 2 a ) and is required for MLL 4 's nucleosomal methyltransferase activity and MLL 4 -mediated differentiation . Kabuki syndrome mutations in PHD (4 -6 ) reduce PHD (4 -6 )'s binding ability and MLL 4 's catalytic activity . PHD (4 -6 )'s binding strength is inhibited by H 4 R 3 symmetric dimethylation (H 4 R 3 me 2 s ), a gene -repressive mark . The protein arginine methyltransferase 7 (PRMT 7 ), but not PRMT 5 , represses MLL 4 target genes by up-regulating H 4 R 3 me 2 s levels and antagonizes MLL 4 -mediated differentiation . Consistently , PRMT 7 knockdown increases MLL 4 -catalyzed H 3 K 4 me 3 levels . During differentiation , decreased H 4 R 3 me 2 s levels are associated with increased H 3 K 4 me 3 levels at a cohort of genes , including many HOXA and HOXB genes . These findings indicate that the trans-tail inhibition of MLL 4 -generated H 3 K 4 me 3 by PRMT 7 -regulated H 4 R 3 me 2 s may result from H 4 R 3 me 2 s 's interference with PHD (4 -6 )'s binding activity and is a novel epigenetic mechanism that underlies opposing effects of MLL 4 and PRMT 7 on cellular differentiation .

Diseases
Validation

Diseases presenting "leukemia" symptom

canavan disease

cholangiocarcinoma

cutaneous mastocytosis

erdheim-chester disease

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

hodgkin lymphoma, classical

junctional epidermolysis bullosa

kabuki syndrome

liposarcoma

monosomy 21

neuralgic amyotrophy

papillon-lefèvre syndrome

phenylketonuria

pleomorphic liposarcoma

pyomyositis

severe combined immunodeficiency

typhoid

waldenström macroglobulinemia

werner syndrome

wiskott-aldrich syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated