Histone Chaperone HIRA facilitates transcription elongation to regulate insulin sensitivity and obesity-associated adipose expansion

Adipose tissue is essential for maintaining glucose and lipid homeostasis in mammals. The histone chaperone HIRA has been reported to play a lineage- and stage-selective role during development. However, its role in adipose tissue development and function as well as its working mechanism remain unknown. Here we show that tissue-specific knockout of histone chaperone HIRA in mice impairs insulin sensitivity and alleviates adipose tissue expansion during high-fat diet-induced obesity, but only moderately affects embryonic development of adipose tissue. Mechanistically, HIRA is selectively required for expression of genes critical for insulin response and lipogenesis, rather than adipogenesis, in adipose tissue. By acute depletion of HIRA protein and by mapping HIRA genomic localization in adipocytes, we demonstrate that HIRA binds to promoters and enhancers of insulin response and lipogenesis genes and regulates their expression by facilitating transcription elongation. Our findings not only identify HIRA as an epigenomic regulator of insulin sensitivity, lipogenesis, and obesity-associated adipose expansion, but also reveal a novel mechanism by which HIRA regulates transcription. Bullet points- HIRA depletion reduces expression of insulin response and lipogenesis genes in adipose tissue - HIRA depletion alleviates adipose tissue expansion during high-fat diet-induced obesity - HIRA targets insulin response and lipogenesis genes in adipocytes - Acute depletion of HIRA impairs transcription elongation on target genes