HIF-1α coordinates epigenetic activation of SIAH1 in hepatocytes in response to nutritional stress

Abstract

Hypoxia inducible factor 1 alpha (HIF-1α) regulates a diverse range of pathophysiological processes. It has been demonstrated previously that HIF-1α plays a role in the pathogenesis of steatosis mediating the effects of excessive nutritional insults. In the present study we investigated the role of HIF-1α in trans‑activating the seven in absentia homolog 1 (SIAH1) gene and the underlying mechanism. We report that in response to nutritional stress, SIAH1 expression was up-regulated in the liver in mice and in cultured hepatocytes. In the meantime, HIF-1α started to occupy the SIAH1 promoter. Depletion of HIF-1α with siRNA or inhibition of HIF-1α with chetomin abrogated the induction of SIAH1 expression. HIF-1α knockdown or inhibition paralleled epigenetic alterations surrounding the SIAH1 promoter characterized by the loss of acetylated histone H3 and trimethylated H3K4 as well as the acquisition of dimethylated H3K9. Further analyses revealed that HIF-1α interacted with and recruited the histone demethylase KDM3A to the SIAH1 promoter to activate transcription. HIF-1α also mediated the crosstalk between KDM3A and p300. Depletion of KDM3A coincided with the loss of SIAH1 induction and the accumulation of dimethylated H3K9 surrounding the SIAH1 promoter. Interestingly, KDM3A expression was also up-regulated by nutritional stress in a HIF-1α dependent manner. Together, our data uncover a novel epigenetic pathway that may contribute to the regulation of SIAH1 expression and the pathogenesis of steatosis.