BRD8 Guards the Pluripotent State by Sensing and Maintaining Histone Acetylation

Area of Science:

• Epigenetics
• Developmental Biology
• Stem Cell Biology

Background:

• Epigenetic mechanisms are crucial for maintaining cell fate stability and directing differentiation during embryonic development.
• The precise roles of epigenetic regulators, like histone acetyltransferase reader proteins, in controlling cell transitions remain incompletely understood.

Purpose of the Study:

• To investigate the function of BRD8, a histone acetyltransferase reader protein, in the conversion between primed mouse epiblast stem cells (EpiSCs) and naive mouse embryonic stem cells (ESCs).
• To elucidate the molecular mechanisms by which BRD8 influences chromatin states and gene expression during cell fate transitions.

Main Methods:

• CRISPR-mediated gene editing to reduce Brd8 expression in mouse EpiSCs.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to assess histone acetylation and chromatin accessibility.
• Analysis of gene expression patterns associated with primed and naive cell states.

Main Results:

• Reduced Brd8 expression impaired the conversion of primed EpiSCs to naive ESCs.
• BRD8 maintains histone acetylation at promoters and gene bodies, contributing to open chromatin at somatic genes and histone acetylation at naive-specific genes.
• Lowering Brd8 levels led to reduced histone acetylation at primed-specific genes and accelerated chromatin accessibility changes at naive-specific genes.
• Active histone deacetylation was identified as a requirement for efficient primed-to-naive cell conversion.

Conclusions:

• BRD8 acts as a critical epigenetic regulator that reads histone acetylation states to control cell fate stability.
• The protein BRD8 influences genome-wide binding of the histone acetyltransferase KAT5, impacting chromatin dynamics.
• This study reveals how BRD8's function in reading histone acetylation both enables and hinders stem cell differentiation and cell type conversion.