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

Abstract

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 G1 cell cycle arrest, accompanied by up‐regulation of the cyclin‐dependent kinase inhibitor p21Cip. Notably, concomitant genetic inactivation of p53 or p21Cip indicates that Hdac1 and Hdac2 regulate p53–p21Cip‐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.

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

“…32 Combined deletion of Hdac1 and Hdac2, or inactivation of their deacetylase activity in primary or oncogenic-transformed fibroblasts, results in a senescence-like G1 cell cycle arrest, accompanied by upregulation of the cyclin-dependent kinase inhibitor P21 and P53. 80 A similar situation is also observed in one-cell embryos; reduction in maternal Hdac1 combined with Hdac2 deficiency (Hdac1 − /+ /Hdac2 −/− ) in fertilized eggs results in developmental arrest from 1-cell to 2-cell transition due to a cell cycle block in G1. 46 However, the cell cycle block is not caused by upregulation of any CDK inhibitors, but rather due to failing to replicate DNA, 46 pointing to different mechanisms of HDAC1 and HDAC2 in cell cycle regulation in different cell types or tissues.…”

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

“…Of note, treatment of patients with HDAC inhibitors results in thrombocytopenia (Prince et al, 2009) and combined Hdac1 and Hdac2 deficiency results in megakaryocyte apoptosis and thrombocytopenia in mice (Wilting et al, 2010). Although it remains unknown whether the thrombocytopenia observed in p45NF-E2-deficient mice is related to altered acetylation, we establish that the placental phenotype and IUGR of p45NF-E2 -/-embryos are mechanistically linked to acetylation-dependent syncytiotrophoblast differentiation.…”

Structure of the 30-kDa Sin3-associated Protein (SAP30) in Complex with the Mammalian Sin3A Corepressor and Its Role in Nucleic Acid Binding

“…In contrast, the larger 1.2-2-MDa Rpd3L/Sin3L complex is recruited to promoter regions to effect transcriptional repression of a wide variety of genes involved in cell cycle control, differentiation, DNA replication and repair, mitochondrial metabolism, and apoptosis (13-20). Consistent with the broad impact of these Rpd3/Sin3 complexes on cellular physiology, sin3 or hdac1/ hdac2 knockouts in mammals have been shown to lead to embryonic lethality or developmental defects (14,15,(21)(22)(23)(24)(25).…”

“…In contrast, the larger 1.2-2-MDa Rpd3L/Sin3L complex is recruited to promoter regions to effect transcriptional repression of a wide variety of genes involved in cell cycle control, differentiation, DNA replication and repair, mitochondrial metabolism, and apoptosis (13-20). Consistent with the broad impact of these Rpd3/Sin3 complexes on cellular physiology, sin3 or hdac1/ hdac2 knockouts in mammals have been shown to lead to embryonic lethality or developmental defects (14,15,(21)(22)(23)(24)(25).Besides the paralogous proteins, including HDAC1/HDAC2, mSin3A/mSin3B, and the histone-interacting RbAp46/ RbAp48 proteins, the mammalian Rpd3L/Sin3L complex comprises at least five other subunits, including SAP30, Sds3, SAP180/RBP1, SAP130, and ING1b/ING2, whose precise roles at the molecular level are poorly understood but most likely involve targeting the complex to specific genomic loci via one or more interaction surfaces (16 -20, 26). The SAP30 subunit was among the first subunits of the complex to be identified and biochemically characterized (17,20) and has since then been consistently detected in fractionation experiments involving this complex (13, 16, 26 -28).…”