Maturity-Onset Diabetes of the Young Type 1 (MODY1)-Associated Mutations R154X and E276Q in Hepatocyte Nuclear Factor 4α (HNF4α) Gene Impair Recruitment of p300, a Key Transcriptional Coactivator

Hepatocyte nuclear factor 4α (HNF4α) is a nuclear receptor involved in glucose homeostasis and is required for normal β-cell function. Mutations in the HNF4α gene are associated with maturity-onset diabetes of the young type 1. E276Q and R154X mutations were previously shown to impair intrinsic transcriptional activity (without exogenously supplied coactivators) of HNF4α. Given that transcriptional partners of HNF4α modulate its intrinsic transcriptional activity and play crucial roles in HNF4α function, we investigated the effects of these mutations on potentiation of HNF4α activity by p300, a key coactivator for HNF4α. We show here that loss of HNF4α function by both mutations is increased through impaired physical interaction and functional cooperation between HNF4α and p300. Impairment of p300-mediated potentiation of HNF4α transcriptional activity is of particular importance for the E276Q mutant since its intrinsic transcriptional activity is moderately affected. Together with previous results obtained with chicken ovalbumin upstream promoter-transcription factor II, our results highlight that impairment of recruitment of transcriptional partners represents an important mechanism leading to abnormal HNF4α function resulting from the MODY1 E276Q mutation. The impaired potentiations of HNF4α activity were observed on the promoter of HNF1α, a transcription factor involved in a transcriptional network and required for β-cell function. Given its involvement in a regulatory signaling cascade, loss of HNF4α function may cause reduced β-cell function secondary to defective HNF1α expression. Our results also shed light on a better structure-function relationship of HNF4α and on p300 sequences involved in the interaction with HNF4α.