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Loss of histone acetyltransferase cofactor transformation/transcription domain‐associated protein impairs liver regeneration after toxic injury
Author(s) -
Shukla Vivek,
Cuenin Cyrille,
Dubey Nileshkumar,
Herceg Zdenko
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24120
Subject(s) - histone acetyltransferase , biology , microbiology and biotechnology , p300 cbp transcription factors , cyclin a , cyclin d1 , cyclin dependent kinase , transcription factor , cancer research , histone , histone deacetylase , cell cycle , histone acetyltransferases , genetics , cell , gene
Organ regeneration after toxin challenge or physical injury requires a prompt and balanced cell‐proliferative response; a well‐orchestrated cascade of gene expression is needed to regulate transcription factors and proteins involved in cell cycle progression and cell proliferation. After liver injury, cell cycle entry and progression of hepatocytes are believed to require concerted efforts of transcription factors and histone‐modifying activities; however, the actual underlying mechanisms remain largely unknown. The purpose of our study was to investigate the role of the histone acetyltransferase (HAT) cofactor transformation/transcription domain‐associated protein (TRRAP) and histone acetylation in the regulation of cell cycle and liver regeneration. To accomplish our purpose, we used a TRRAP conditional knockout mouse model combined with toxin‐induced hepatic injury. After we treated the mice with a carbon tetrachloride toxin, conditional ablation of the TRRAP gene in those mice severely impaired liver regeneration and compromised cell cycle entry and progression of hepatocytes. Furthermore, loss of TRRAP impaired the induction of early and late cyclins in regenerating livers by compromising histone acetylation and transcription factor binding at the promoters of the cyclin genes. Our results demonstrate that TRRAP and TRRAP/HAT‐mediated acetylation play an important role in liver regeneration after toxic injury and provide insight into the mechanism by which TRRAP/HATs orchestrate the expression of the cyclin genes during cell cycle entry and progression. (H EPATOLOGY 2011)