Effects of interactions of hepatocyte nuclear factor 4α isoforms with coactivators and corepressors are promoter‐specific

Abstract

The gene encoding hepatocyte nuclear factor 4K K (HNF4K K) possesses two alternative promoters responsible for developmental and tissue-speci¢c expression of HNF4K K1 and HNF4K K7. The two isoforms possess di¡erent N-termini and exhibit distinct transactivation properties. We show here for the ¢rst time that the e¡ects mediated by HNF4K K isoforms in concert with three di¡erent coregulators result in promoter-speci¢c responses. Transcript levels of silencing mediator for retinoid and thyroid receptors and glucocorticoid receptor interacting protein-1 in the liver are reduced at birth, a time point when many genes are strongly activated, suggesting that the e¡ects of coregulators on HNF4K K activity in vivo could be determined by the levels of their expression as well as by the target promoter.

Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1α Are Required for Time-Specific Gene Expression during Liver Development

“…This highlights the promoter specificity of HNF-6-coactivator interactions. A similar promoter-specific HNF-4-coactivator interaction had been illustrated previously for HNF-4-SMRT interactions (44). On the other hand, PGC-1␣ is a known coactivator of HNF-4 (49), and we now show that PGC-1␣ is efficiently recruited to the g6pc promoter by HNF-6 and HNF-4, raising the possibility that a trimeric HNF-6/HNF-4/PGC-1␣ complex is formed.…”

Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

“…While there are a few reports on the differential activity of the HNF4␣ isoforms (22,(93)(94)(95), to our knowledge, this is the first in-depth functional comparison of the HNF4␣ isoforms in a colon cancer line. Likewise, while there are reports of interactions between HNF4␣ and TCF4 (12,31,(40)(41)(42)(43)(44)(45), this is the first report to examine the effect of the presence of the HNF4␣ isoforms on TCF4 chromatin binding, identify a potential three-way interaction between HNF4␣, TCF4, and AP-1, and examine in great depth the DNA binding specificity of the HNF4␣ isoforms and TCF4.…”

Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation and stem cell reprogrammation

“…In detail, HNF-4a, directly interacts with SRC1, CBP and p300, resulting in its increased transcriptional activity [86][87][88][89][90][91][92]. The level of upregulation is isoform-dependent [92,93]. In human hepatoma cells, transactivation of CYP1A1, CYP1A2 and CYP2C9 by HNF-4a relies on the presence of the PPAR-gamma coactivator 1alpha (PGC-1a) [94].…”