title: Loss of histone deacetylases 1 and 2 in hepatocytes impairs murine liver regeneration through Ki67 depletion.
abstract: Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G1 phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down-regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein β.
  
  
  CONCLUSIONS
  Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration.
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Chengdu, China; State Key Laboratory of Biotherapy, Chengdu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xia
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhou
authors.forename: Hongjie
authors.initials: H
authors.lastname: Ji
authors.forename: Yujia
authors.initials: Y
authors.lastname: Wang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Ji
authors.initials: J
authors.lastname: Bao
authors.forename: Feng
authors.initials: F
authors.lastname: Ye
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shi
authors.forename: Hong
authors.initials: H
authors.lastname: Bu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002252:Carbon Tetrachloride Poisoning; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006498:Hepatectomy; D056284:Histone Deacetylase 1 / Q000172:deficiency*; D056464:Histone Deacetylase 2 / Q000172:deficiency*; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis
chemical_list: D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2