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BRD2 impedes iPSC reprogramming by regulating lipogenesis and matrisome.

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BRD2 suppresses lipogenesis, hindering human pluripotent stem cell (HiPSC) reprogramming. Enhancing lipogenesis or supplementing lipids promotes HiPSC generation, revealing BRD2

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Area of Science:

  • Stem Cell Biology
  • Epigenetics
  • Metabolic Regulation

Background:

  • Human pluripotent stem cell (HiPSC) induction from somatic cells faces poorly understood barriers.
  • The role of lipids in cellular reprogramming remains largely unexplored.
  • BRD2's function in regulating lipogenesis and the matrisome program during reprogramming is unknown.

Purpose of the Study:

  • To investigate the role of BRD2 in human pluripotent stem cell (HiPSC) reprogramming.
  • To elucidate the mechanisms by which BRD2 influences lipogenesis and the matrisome program.
  • To determine if modulating lipogenesis can overcome reprogramming barriers.

Main Methods:

  • Assessing BRD2's impact on lipogenesis and somatic transcriptional programs during reprogramming.
  • Analyzing the effects of SCD and HMGCR (lipogenesis enzymes) on iPSC reprogramming.
  • Investigating the influence of lipid supplementation on reprogramming efficiency.
  • Examining BRD2's binding to lipogenesis genes and its regulation of H3K27Ac status.

Main Results:

  • BRD2 acts as a barrier to HiPSC reprogramming by suppressing lipogenesis.
  • BRD2 maintains the somatic transcriptional program, including the matrisome program.
  • Upregulating lipogenesis enzymes (SCD, HMGCR) or supplementing lipids enhances iPSC reprogramming.
  • BRD2's ET tail suppresses reprogramming and lipogenesis but positively regulates the matrisome program.
  • BRD2 binds to lipogenesis genes and negatively regulates their H3K27Ac levels.

Conclusions:

  • BRD2 suppresses lipogenesis, presenting a barrier to HiPSC reprogramming.
  • Targeting lipogenesis pathways or lipid supplementation can promote HiPSC generation.
  • BRD2 exhibits opposing regulatory roles on matrisome and lipogenesis, impacting reprogramming outcomes.