Inhibitor of DNA binding/differentiation 4 deficiency impairs hepatic fatty acid synthesis and is associated with epigenomic alterations in chromatin accessibility

Inhibitor of DNA binding/differentiation (ID) 4 is a member of the ID family of proteins. ID4 is involved in gene transcriptional regulation during diverse pathophysiological processes, including cellular differentiation, proliferation, and senescence. ID4-deficient (Id4^−/−) mice exhibit markedly reduced tissue and body mass and survive for only a few weeks after birth. However, the direct cause of this premature lethality remains unknown. This study demonstrated that ID4 deficiency leads to impaired hepatic fatty acid synthesis, accompanied by downregulation of the rate-limiting enzymes of fatty acid synthesis, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1). Comprehensive histone modification profiling based on mass spectrometry revealed drastic alterations involving histone modification patterns in the livers of Id4^−/−mice compared to those of wild-type littermates. Furthermore, ID4 deficiency resulted in aberrant histone expression patterns. Integrative assay for transposase-accessible chromatin sequencing and RNA-sequencing analyses further revealed that ID4 deficiency induces chromatin closure at the promoter region of Srebf1 (encoding sterol regulatory element-binding protein), a master transcription factor upstream of Fasn (encoding FASN) and Acaca (encoding ACC1). Collectively, these findings indicate that ID4 functions as an important regulator of hepatic fatty acid metabolism by maintaining chromatin accessibility, rather than merely acting as a classical ID protein that regulates target gene transcription.