title: Histone arginine methylation keeps RUNX1 target genes in an intermediate state.
abstract: The coordinated recruitment of epigenetic regulators of gene expression by transcription factors such as RUNX1 (AML1, acute myeloid leukemia 1) is crucial for hematopoietic differentiation. Here, we identify protein arginine methyltransferase 6 (PRMT6) as a central functional component of a RUNX1 corepressor complex containing Sin3a and HDAC1 in human hematopoietic progenitor cells. PRMT6 is recruited by RUNX1 and mediates asymmetric histone H3 arginine-2 dimethylation (H3R2me2a) at megakaryocytic genes in progenitor cells. H3R2me2a keeps RUNX1 target genes in an intermediate state with concomitant H3K27me3 and H3K4me2 but not H3K4me3. Upon megakaryocytic differentiation PRMT6 binding is lost, the H3R2me2a mark decreases and a coactivator complex containing WDR5/MLL and p300/pCAF is recruited. This leads to an increase of H3K4me3 and H3K9ac, which result in augmented gene expression. Our results provide novel mechanistic insight into how RUNX1 activity in hematopoietic progenitor cells maintains differentiation genes in a suppressed state but poised for rapid transcriptional activation.
authors: Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt am Main, Germany.
authors: J
authors: J
authors: Herglotz
authors: O N
authors: ON
authors: Kuvardina
authors: S
authors: S
authors: Kolodziej
authors: A
authors: A
authors: Kumar
authors: H
authors: H
authors: Hussong
authors: M
authors: M
authors: Grez
authors: J
authors: J
authors: Lausen
mesh_terms: D001120:Arginine / Q000378:metabolism*; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D055016:Megakaryocyte Progenitor Cells / Q000502:physiology; D008533:Megakaryocytes / Q000378:metabolism; D008745:Methylation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D001120:Arginine; D050676:Core Binding Factor Alpha 2 Subunit; D056284:Histone Deacetylase 1; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011484:Protein-Arginine N-Methyltransferases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C493728:RUNX1 protein, human; C502547:WDR5 protein, human; C447833:PRMT6 protein, human; C110550:HDAC1 protein, human