The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis

Cell Rep. 2014 May 22;7(4):1239-47. doi: 10.1016/j.celrep.2014.04.015. Epub 2014 May 9.

Abstract

Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here, we show that the SET domain, and thus HMT activity of MLL1, is dispensable for maintaining HSCs and supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation is selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 is sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • Hematopoiesis / genetics
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Mice
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Histone Acetyltransferases
  • MOF protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1

Associated data

  • GEO/GSE56456