title: Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice.
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.
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Dovey
authors.forename: Charles T
authors.initials: CT
authors.lastname: Foster
authors.forename: Nathalie
authors.initials: N
authors.lastname: Conte
authors.forename: Sally A
authors.initials: SA
authors.lastname: Edwards
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Edwards
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: George
authors.initials: G
authors.lastname: Vassiliou
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Cowley
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology; D002843:Chromatin / Q000235:genetics; D002869:Chromosome Aberrations; D004249:DNA Damage / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D042822:Genomic Instability / Q000235:genetics* / Q000276:immunology; D057895:Haploinsufficiency / Q000235:genetics / Q000276:immunology; D056284:Histone Deacetylase 1 / Q000235:genetics* / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D013950:Thymus Gland / Q000166:cytology; D059467:Transcriptome / Q000276:immunology
chemical_list: D002843:Chromatin; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2