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Hepatocyte nuclear factor 4 alpha (HNF4α), a member of the nuclear receptor superfamily, is essential for liver function and is linked to several diseases including diabetes, hemophilia, atherosclerosis, and hepatitis. Although many DNA response elements and target genes have been identified for HNF4α, the complete repertoire of binding sites and target genes in the human genome is unknown. Here, we adapt protein binding microarrays (PBMs) to examine the DNA‐binding characteristics of two HNF4α species (rat and human) and isoforms (HNF4α2 and HNF4α8) in a high‐throughput fashion. We identified ∼1400 new binding sequences and used this dataset to successfully train a Support Vector Machine (SVM) model that predicts an additional ∼10,000 unique HNF4α‐binding sequences; we also identify new rules for HNF4α DNA binding. We performed expression profiling of an HNF4α RNA interference …