title: Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells.
abstract: Histone deacetylases 1 and 2 (HDAC1/2) form the core catalytic components of corepressor complexes that modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an ES cell line in which Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 resulted in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is dependent upon cell cycle progression, because differentiated, nonproliferating cells retain their viability. Furthermore, we observe increased mitotic defects, chromatin bridges, and micronuclei, suggesting HDAC1/2 are necessary for accurate chromosome segregation. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2-deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog, Esrrb, and Rex1. HDAC1/2 activity is regulated through binding of an inositol tetraphosphate molecule (IP4) sandwiched between the HDAC and its cognate corepressor. This raises the important question of whether IP4 regulates the activity of the complex in cells. By rescuing the viability of double-knockout cells, we demonstrate for the first time (to our knowledge) that mutations that abolish IP4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors.
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
authors: Shereen
authors: S
authors: Jamaladdin
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
authors: Richard D W
authors: RD
authors: Kelly
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
authors: Laura
authors: L
authors: O'Regan
authors: Wellcome Trust Sanger Institute, Hinxton, Cambs CB10 1SA, United Kingdom.
authors: Oliver M
authors: OM
authors: Dovey
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
authors: Grace E
authors: GE
authors: Hodson
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
authors: Christopher J
authors: CJ
authors: Millard
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
authors: Nicola
authors: N
authors: Portolano
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
authors: Andrew M
authors: AM
authors: Fry
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
authors: John W R
authors: JW
authors: Schwabe
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; and smc57@le.ac.uk.
authors: Shaun M
authors: SM
authors: Cowley
mesh_terms: D000107:Acetylation; D000818:Animals; D002455:Cell Division / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000502:physiology*; D056464:Histone Deacetylase 2 / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D006657:Histones; D014157:Transcription Factors; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2