Histone acetyltransferase p300 has been implicated in the regulation of liver biology; however, molecular mechanisms of this regulation are not known. In this paper, we examined these mechanisms using transgenic mice expressing a dominant negative p300 molecule (dnp300 mice). While dnp300 mice did not show abnormal growth within 1 year; these mice have many alterations in liver biology and liver functions. We found that the inhibition of p300 leads to accumulation of heterochromatin foci in the liver of two-month old mice. RNA-Seq analysis showed that this inhibition of p300 also causes alteration of gene expression in many signaling pathways including chromatin remodeling, apoptosis, DNA damage, translation an... More
Histone acetyltransferase p300 has been implicated in the regulation of liver biology; however, molecular mechanisms of this regulation are not known. In this paper, we examined these mechanisms using transgenic mice expressing a dominant negative p300 molecule (dnp300 mice). While dnp300 mice did not show abnormal growth within 1 year; these mice have many alterations in liver biology and liver functions. We found that the inhibition of p300 leads to accumulation of heterochromatin foci in the liver of two-month old mice. RNA-Seq analysis showed that this inhibition of p300 also causes alteration of gene expression in many signaling pathways including chromatin remodeling, apoptosis, DNA damage, translation and activation of cell cycle. Livers of dnp300 mice have a high rate of proliferation and much higher rate of proliferation after partial hepatectomy. We found that livers of dnp300 mice are resistant to CCl4-mediated injury and have reduced apoptosis, but have increased proliferation after injury. Under-laying mechanisms of resistance to liver injury and increased proliferation in dnp300 mice include ubiquitin proteasome-mediated degradation of C/EBPα and translational repression of p53 protein by CUGBP1-eIF2 repressor complex. Our data demonstrate that p300 regulates a number of critical signaling pathways which control liver functions.
