Chromatin remodeling and H3K4me3 depletion regulate germline specification from pluripotency

Germ cells are the only cells capable of transmitting heritable genetic material to future generations. Epigenetic mechanisms that regulate germ cell formation are essential for optimizing offspring production, which is particularly important in farm animals like chicken. Primordial germ cells (PGCs), the precursors of gametes, could be derived from the pluripotent blastoderm cells (BC) or embryonic stem cell (ESCs) in chicken but the germline induction efficiency remain low and require further improvements.

We systematically profiled key histone modifications and chromatin states during the germ/soma specification from chicken pluripotent blastoderm cells to either PGCs or fibroblasts to uncover the chromatin regulators that direct the germline specification. The histone methyltransferase was perturbed during germ cell differentiation to assess the effect of histone modification on germline induction.

The specific alterations of chromatin states could instruct the expression of germline genes and repress the pluripotency or somatic gene program in distinct cell types. The dynamic chromatin activation at both promoters and enhancers contribute to germline induction from pluripotency. Interestingly, the diminished active histone modification H3K4me3 regulate the transitions of bivalent states into repressive to facilitate the specification of the germ cell lineage. We demonstrated that selectively erase the H3K4me3 modifications could block the expression of BMP signaling antagonists, thereby enhancing the creation of PGC-like cells (PGCLCs) in chicken.

The comprehensive analysis of gene expression and chromatin regulation patterns during germ/soma segregation reveals that chromatin reprogramming mechanisms play crucial roles in controlling germline specification. This research also provides new epigenetic strategies to enhance the production of germ cells.