Cells with the same DNA can develop specialized functions during embryonic development, regulated by epigenetic mechanisms driven by transcription factors (TFs) and epigenetic factors. Identifying epigenetic barriers to cell-type conversions remains challenging. Research on somatic cell reprogramming has revealed such barriers, involving extensive developmental changes.

A more practical model for studying these processes is the interconversion between mouse naïve embryonic stem cells (ESCs), resembling pre-implantation blastocysts, and primed epiblast stem cells (EpiSCs), resembling post-implantation epiblasts. These states require distinct signaling conditions, with naïve-to-primed transitions being efficient, but primed-to-naïve reversion inefficient.

Although both states share regulatory modules, like OCT4 and SOX2, they also have distinct TFs, such as OTX2 in EpiSCs and KLF4 in ESCs. This divergence suggests that epigenetic roadblocks may hinder reversion to earlier developmental stages. Despite progress in understanding these transitions, the mechanisms underlying these barriers and their role in resisting cell fate conversions remain poorly understood.

A research team led by Associate Professor Andrew P. Hutchins from the Department of Systems Biology, School of Life Sciences at the Southern University of Science and Technology (SUSTech) has revealed the core mechanism of how the epigenetic factor BRD8 regulates the pluripotent state of stem cells by sensing and maintaining histone acetylation.

Their paper, titled “BRD8 Guards the Pluripotent State by Sensing and Maintaining Histone Acetylation”, has been published in the journal Advanced Science.

Their investigations reveal that BRD8 plays a critical role in regulating histone acetylation at promoter and transcription regions, influencing stem cell fate transitions. BRD8 maintains chromatin openness in somatic cell-related gene regions and preserves histone acetylation of primed-specific genes, preventing the transition from a primed to a naïve pluripotent state. Reduced BRD8 expression does not alter chromatin accessibility but decreases histone acetylation levels in primed-specific genes. During the cell-type transition process, this reduction accelerates chromatin accessibility and the expression of naïve-specific genes, thereby promoting the transition to a naïve state.

Additionally, the study identifies that BRD8’s role in regulating stem cell fate transitions depends on the acetyltransferase activity of KAT5. As a histone acetylation “reader”, BRD8 enables the precise genomic localization of KAT5, ensuring cellular homeostasis.

Their research elucidates the critical regulatory role of BRD8 in the transition of mouse embryonic stem cells from a primed to a naïve state. It highlights how BRD8 stabilizes cell identity by sensing and maintaining histone acetylation, thereby controlling stem cell differentiation. These findings provide a fresh perspective on BRD8’s regulatory role in stem cells, offering new insights into core regulatory mechanisms and paving the way for advancements in regenerative medicine and disease treatment.

Li Sun, a former postdoctoral researcher at SUSTech and currently at IRCBC, CAS, and Xiuling Fu, a former doctoral student at SUSTech and currently a postdoctoral researcher at Columbia University, are the co-first authors of the paper. Associate Professor Andrew P. Hutchins is the corresponding author. Valuable insights were provided by Associate Professor Ralf Jauch from the University of Hong Kong and Professor Dongwei Li from the Fifth Affiliated Hospital of Guangzhou Medical University.

Paper link: https://advanced.onlinelibrary.wiley.com/doi/full/10.1002/advs.202409160