BRD2 impedes iPSC reprogramming by regulating lipogenesis and matrisome

Induction of human pluripotent stem cells (HiPSCs) from somatic cells encounters significant barriers, which remain poorly understood. Lipids are fundamental cellular molecules with many essential roles. However, lipid roles in reprogramming are unknown. Here, we prove that BRD2 is a barrier to HiPSC reprogramming by suppressing lipogenesis and maintaining the somatic transcriptional program, particularly the somatic matrisome program. Strikingly, the acetylation epigenetic reader BRD2 unorthodoxically suppressed gene expression of lipogenesis in the reprogramming cells. The two rate-limiting enzymes of lipogenesis, SCD and HMGCR, enhanced iPSC reprogramming while lipid supplements enhanced it. Interestingly, the BRD2 ET tail suppressed reprogramming and the lipogenesis transcriptional program but positively regulated matrisome program. In line with its transcriptional suppression of lipogenesis, BRD2 binds to genes of lipogenesis and negatively regulates their H3K27Ac status. These discoveries advance our knowledge of HiPSC reprogramming by revealing the opposite BRD2 regulatory roles on matrisome and lipogenesis in promoting reprogramming.