HDAC7 is a repressor of myeloid genes whose downregulation is required for transdifferentiation of pre-B cells into macrophages

PLoS Genet. 2013 May;9(5):e1003503. doi: 10.1371/journal.pgen.1003503. Epub 2013 May 16.

Abstract

B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism
  • Binding Sites
  • Cell Differentiation
  • Cell Lineage
  • Cell Transdifferentiation / genetics*
  • Down-Regulation
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Humans
  • Lymphopoiesis*
  • MADS Domain Proteins / metabolism
  • MEF2 Transcription Factors
  • Macrophages / cytology*
  • Macrophages / metabolism
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • Myogenic Regulatory Factors / metabolism
  • Precursor Cells, B-Lymphoid / cytology*
  • Precursor Cells, B-Lymphoid / metabolism
  • Promoter Regions, Genetic

Substances

  • MADS Domain Proteins
  • MEF2 Transcription Factors
  • MEF2C protein, human
  • Myogenic Regulatory Factors
  • HDAC7 protein, human
  • Histone Deacetylases

Grant support

This work was supported by a grant from the Spanish Ministry of Science and Innovation (MICIIN) (BFU2008-00410) (to MP), a grant from the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2011-28290) (to MP), and a Marie Curie IRG grant from the European Commission (FP7-MIRG-CT-2007-208119) (to MP). MP was supported by a Ramon y Cajal contract from the Spanish Ministry of Science and Innovation (MICIIN). LR-G was supported by an IDIBELL PhD fellowship. ABMMKI was supported by fellowship from AGAUR, Catalonian Government, Spain. TM was supported by an Erasmus MC Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.