P/CAF modulates the activity of the transcription factor p48/PTF1a involved in pancreatic acinar differentiation
Résumé
p48, also called Ptf1a, is a tissue-restricted basic helix-loop-helix transcription factor critical for pancreatic commitment during development and for the activation/maintenance of the acinar differentiation program in exocrine pancreas. High-level expression of exocrine digestive enzymes, a hallmark of mature acinar cells, depends largely on the trimeric complex PTF1 (pancreas transcription factor 1), formed by p48, RBP-L and a class A bHLH protein. In addition, p48 induces cell cycle exit by controlling G1-S progression. However, the mechanisms that mediate the PTF1-dependent gene activation are poorly understood. Here, we report that p48 increases transcription through two activation domains located in its N-terminal region by recruiting transcriptional coactivators. The histone acetyltransferase cofactor p/CAF interacts in vivo with p48 in acinar cells and is associated with the promoter region of acinar genes targeted by the PTF1 complex. P/CAF potentiates the PTF1 transcriptional activity by selectively enhancing the p48 transactivation activity. P/CAF promotes the nuclear accumulation of p48 and its in vivo acetylation in Lys residue K200. The K200R mutation abolishes the transcriptional activity of p48 as well as its capacity to functionally cooperate with RBP-L to ensure an effective PTF1-driven transcription, indicating that p/CAF-mediated acetylation of p48 is required for PTF1 full transcriptional activity. By contrast, p/CAF did not cooperate with p48 in its growth regulatory effects. These results support a critical and selective role of p/CAF in the PTF1-dependent gene activation during acinar differentiation.
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