1 Liver regeneration is maintained through the orchestration of regenerative signaling pathways involving an interplay between nonparenchymal check details and parenchymal cells.22 Therefore, our results suggest that the failure of TRRAP-deficient livers to regenerate may be caused by proliferation defects in both hepatocytes and nonparenchymal cells. However,

further studies are needed to determine to what extent the proliferation defect in nonparenchymal cells may contribute to the TRRAP-deficient phenotype induced by liver injury. Along with the defect in hepatocyte proliferation in TRRAP-CKO livers, we found a striking defect in the induction of cyclin D1/2, cyclin E, and cyclin A. These findings suggest that in regenerating livers, TRRAP is essential for the induction

of both early and late cyclins, although TRRAP appears to be dispensable for expression of CDK genes. Because expression of the cyclin genes, in contrast to the CDK genes, is regulated in a cell cycle stage-specific manner, TRRAP may be involved in the coordinated expression of the cyclin genes needed for cell cycle entry and progression during liver regeneration (Supporting Fig. 2B). D-type cyclins are important for early cell cycle reentry and G1-S progression23, 24; therefore, the defect in cell proliferation of hepatocytes in TRRAP-deficient livers may be due to cellular failure to induce cyclin D1/2 in the absence of TRRAP. Selleck GW 572016 Our findings agree with published data showing that reduced levels of D cyclins are associated with impaired liver regeneration.25-27 Because TRRAP has been shown to bind, together with HATs, to cyclin D promoters to mediate histone acetylation and gene expression,12, 28 our results suggest that during liver regeneration TRRAP regulates cell cycle reentry of hepatocytes through expression of D type cyclins, whereas TRRAP promotes

cell cycle progression through expression of cyclin E and cyclin A. The precise mechanism by which TRRAP mediates transcription of the cyclin genes remains elusive. ChIP analysis click here of the cyclin A promoter revealed significantly lower levels of both histone H3 and H4 acetylation, consistent with previous studies showing that TRRAP regulates expression of genes by acetylation of histone H3 or histone H413, 18 and that TRRAP is important for the integrity and function of HAT complexes.9 Of note, despite a clear trend showing an impaired acetylation in TRRAP-deficient livers, we observed a marked variability in acetylation levels using different amplicons, suggesting that TRRAP-dependent HATs may exhibit differential activity across different regions of the cyclin A promoter. Our study revealed that loss of TRRAP compromised the binding of transcription factors c-Myc and E2F1 at the cyclin gene promoter during liver regeneration. Based on these findings, we propose that TRRAP/HAT-mediated histone acetylation may be a determinant of transcription factor binding (Supporting Fig.