BRD2 impedes iPSC reprogramming by regulating lipid biosynthesis and the matrisome via its ET tail

Induction of human pluripotent stem cells (hiPSCs) from somatic cells encounters significant barriers that remain poorly understood. Lipids are fundamental cellular molecules with many essential roles. However, the roles of lipids in reprogramming are unknown. Here, we show that BRD2 is a barrier to hiPSC reprogramming by suppressing lipid genes and maintaining the somatic transcriptional program, particularly the somatic matrisome program. Strikingly, the acetylation epigenetic reader BRD2 unorthodoxly suppresses the expression of lipid-related genes in the reprogramming cells. The two rate-limiting enzymes of lipid biosynthesis, stearoyl-CoA desaturase (SCD), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), and lipid supplements all enhance iPSC reprogramming. Interestingly, the extra terminal (ET) tail of BRD2 suppresses reprogramming and the lipid transcriptional program but positively regulates the matrisome program. In line with its transcriptional suppression of lipid genes, BRD2 binds to genes of lipid biosynthesis and negatively regulates their H3K27Ac status. These discoveries advance our molecular understanding of hiPSC reprogramming, as well as of the transcriptional regulation of matrisome and lipid programs. BRD2, via its ET tail, impairs iPSC generation in early reprogramming by maintaining the somatic transcription, especially, the somatic matrisome program, and by suppressing lipid biosynthesis. Lipid deficiency is a barrier to reprogramming.