Abstract
Spermatogonial stem and progenitor cells (SSCs) generate adult male gametes. During in vitro expansion, these unipotent murine cells spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Here we investigate this conversion process through integrative transcriptomic and epigenomic analyses. We find in SSCs that promoters essential to maintenance and differentiation of embryonic stem cells (ESCs) are enriched with histone H3-lysine4 and -lysine 27 trimethylations. These bivalent modifications are maintained at most somatic promoters after conversion, bestowing MASCs an ESC-like promoter chromatin. At enhancers, the core pluripotency circuitry is activated partially in SSCs and completely in MASCs, concomitant with loss of germ cell-specific gene expression and initiation of embryonic-like programs. Furthermore, SSCs in vitro maintain the epigenomic characteristics of germ cells in vivo. Our observations suggest that SSCs encode innate plasticity through the epigenome and that both conversion of promoter chromatin states and activation of cell type-specific enhancers are prominent features of reprogramming.
Highlights
Spermatogonial stem and progenitor cells (SSCs) generate adult male gametes
Upon germline specification in the mouse embryo, somatic genes are mainly repressed in primordial germ cells (PGCs), while several embryonic stem cells (ESCs) signature transcription factors exhibit transcriptional activation and their expressions are preserved at modest levels in spermatogonia, which include SSCs in the adult testis[5,6,7]
We first compared global gene expression among multipotent adult spermatogonial-derived stem cells (MASCs), ESCs and induced pluripotent stem (iPS) cells using hierarchical clustering of RNA-seq results collected from each cell type (Supplementary Data 1)
Summary
Spermatogonial stem and progenitor cells (SSCs) generate adult male gametes. During in vitro expansion, these unipotent murine cells spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Mouse SSCs, despite being unipotent, are uniquely capable of abrogating lineage commitment and spontaneously converting to multipotent adult spermatogonial-derived stem cells (MASCs), which share many features with pluripotent embryonic stem cells (ESCs) derived from the inner cell mass (ICM), including the capacity to induce teratomas and contribute to chimeric animals (Fig. 1a)[1,2] To date, this is the only known spontaneous reprogramming event that converts unipotent adult stem cells back to a nearpluripotent state without delivery of exogenous genes or gene products, which distinguishes it from transcription factor-driven conversion of fibroblasts to induced pluripotent stem (iPS) cells[3,4]. To elucidate the epigenomic regulation underlying SSC conversion, we describe the results of chromatin immunoprecipitation followed by sequencing (ChIP-seq) on SSCs and MASCs to identify changes in transcription-associated histone modifications at both promoters and enhancers of reprogrammed genes This genome-wide study reveals that long-term in vitrocultured SSCs, which are capable of unipotent differentiation to all germ cells in mouse testicular transplantation, closely align with MASCs and ESCs in global gene expression and histone modification. Our results reveal the topography of global histone modifications in mouse SSCs and MASCs, and indicate developmental lineageassociated epigenetic signature changes before and after spontaneous SSC cell fate transitions
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