Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis

• Published in: The EMBO journal Vol. 29; no. 15; pp. 2586 - 2597
• Main Authors: Wilting, Roel H, Yanover, Eva, Heideman, Marinus R, Jacobs, Heinz, Horner, James, van der Torre, Jaco, DePinho, Ronald A, Dannenberg, Jan-Hermen
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 04-08-2010; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Anemia - enzymology; Animals; Apoptosis; Biocatalysis; Cell Cycle; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21 - deficiency; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; EMBO06; EMBO09; Erythrocytes; Genetics; haematopoiesis; Hdac1; Hdac2; Hematopoiesis; Histone Deacetylase 1 - deficiency; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - deficiency; Histone Deacetylase 2 - metabolism; Humans; Inactivation; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; p21Cip; Proteins; senescence; Thrombocytopenia - enzymology; Thrombocytopenia - pathology; Tumor Suppressor Protein p53 - metabolism; senescence; Hdac2; Hdac1; haematopoiesis; p21
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2010.136

Histone deacetylases (HDACs) counterbalance acetylation of lysine residues, a protein modification involved in numerous biological processes. Here,
Hdac1
and
Hdac2
conditional knock‐out alleles were used to study the function of class I Hdac1 and Hdac2 in cell cycle progression and haematopoietic differentiation. Combined deletion of Hdac1 and Hdac2, or inactivation of their deacetylase activity in primary or oncogenic‐transformed fibroblasts, results in a senescence‐like G
1
cell cycle arrest, accompanied by up‐regulation of the cyclin‐dependent kinase inhibitor p21
Cip
. Notably, concomitant genetic inactivation of p53 or p21
Cip
indicates that Hdac1 and Hdac2 regulate p53–p21
Cip
‐independent pathways critical for maintaining cell cycle progression.
In vivo
, we show that Hdac1 and Hdac2 are not essential for liver homeostasis. In contrast, total levels of Hdac1 and Hdac2 in the haematopoietic system are critical for erythrocyte‐megakaryocyte differentiation. Dual inactivation of Hdac1 and Hdac2 results in apoptosis of megakaryocytes and thrombocytopenia. Together, these data indicate that Hdac1 and Hdac2 have overlapping functions in cell cycle regulation and haematopoiesis. In addition, this work provides insights into mechanism‐based toxicities observed in patients treated with HDAC inhibitors.