Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis.
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.
Wilting
Roel H
RH
Division of Molecular Genetics, Plesmanlaan 121, Amsterdam, The Netherlands.
Yanover
Eva
E
Heideman
Marinus R
MR
Jacobs
Heinz
H
Horner
James
J
van der Torre
Jaco
J
DePinho
Ronald A
RA
Dannenberg
Jan-Hermen
JH
D000740:Anemia / Q000201:enzymology; D000818:Animals; D017209:Apoptosis; D055162:Biocatalysis; D002453:Cell Cycle; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000378:metabolism; D006410:Hematopoiesis; D056284:Histone Deacetylase 1 / Q000172:deficiency / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013921:Thrombocytopenia / Q000201:enzymology / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2