Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice

  • Dovey O
  • Foster C
  • Conte N
 et al. 
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Abstract

Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T-cell specific deletion. Loss of either HDAC1 or HDAC2 alone has little effect, while dual inactivation results in a 5-fold reduction in thymocyte cellularity, accompanied by developmental arrest at the double-negative to double-positive transition. Transcriptome analysis revealed 892 misregulated genes in Hdac1/2 knock-out thymocytes, including down-regulation of LAT, Themis and Itk, key components of the T-cell receptor (TCR) signaling pathway. Down-regulation of these genes suggests a model in which HDAC1/2 deficiency results in defective propagation of TCR signaling, thus blocking development. Furthermore, mice with reduced HDAC1/2 activity (Hdac1 deleted and a single Hdac2 allele) develop a lethal pathology by 3-months of age, caused by neoplastic transformation of immature T cells in the thymus. Tumor cells become aneuploid, express increased levels of c-Myc and show elevated levels of the DNA damage marker, γH2AX. These data demonstrate a crucial role for HDAC1/2 in T-cell development and the maintenance of genomic stability.

Author-supplied keywords

  • Animals
  • Cell Transformation
  • Chromatin
  • Chromatin: genetics
  • Chromosome Aberrations
  • DNA Damage
  • DNA Damage: genetics
  • DNA Damage: immunology
  • Enzyme Activation
  • Enzyme Activation: genetics
  • Enzyme Activation: immunology
  • Female
  • Genomic Instability
  • Genomic Instability: genetics
  • Genomic Instability: immunology
  • Haploinsufficiency
  • Haploinsufficiency: genetics
  • Haploinsufficiency: immunology
  • Histone Deacetylase 1
  • Histone Deacetylase 1: genetics
  • Histone Deacetylase 1: metabolism
  • Histone Deacetylase 2
  • Histone Deacetylase 2: genetics
  • Histone Deacetylase 2: metabolism
  • Knockout
  • Male
  • Mice
  • Neoplastic
  • Neoplastic: genetics
  • Neoplastic: immunology
  • Newborn
  • Signal Transduction
  • Signal Transduction: genetics
  • Signal Transduction: immunology
  • T-Lymphocytes
  • T-Lymphocytes: cytology
  • T-Lymphocytes: enzymology
  • Thymus Gland
  • Thymus Gland: cytology
  • Transcriptome
  • Transcriptome: immunology

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Authors

  • Oliver M Dovey

  • Charles T Foster

  • Nathalie Conte

  • S. A. Edwards

  • Jennifer M Edwards

  • Rajinder Singh

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