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Relaxed 3D genome conformation facilitates the pluripotent to totipotent-like state transition in embryonic stem cells

ABSTRACT: The 3D genome organization is crucial for gene regulation. Although recent studies have revealed a uniquely relaxed genome conformation in totipotent early blastomeres of both fertilized and cloned embryos, how weakened higher-order chromatin structure is functionally linked to totipotency acquisition remains elusive. Using low-input Hi-C, ATAC-seq, and ChIP-seq, we systematically examined the dynamics of 3D genome and epigenome during pluripotent to totipotent-like state transition in mouse embryonic stem cells (ESCs). The spontaneously converted 2-cell-embryo-like cells (2CLCs) exhibited more relaxed chromatin architecture compared to ESCs, including global weakening of both enhancer-promoter interactions and TAD insulation. While the former correlated with inactivation of ESC enhancers and down-regulation of pluripotent genes, the latter might facilitate contacts between the putative new enhancers arising in 2CLCs and neighboring 2C genes. Importantly, disruption of chromatin organization by depleting CTCF or the cohesin complex promoted the ESC to 2CLC transition. Our results thus establish a critical role of 3D genome organization in totipotency acquisition.

ORGANISM(S): Mus musculus

PROVIDER: GSE159623 | GEO | 2021/10/20

REPOSITORIES: GEO

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Project description:Mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) exhibit a pluripotent developmental potential, contributing to all embryonic cell types, though rarely to extra-embryonic lineages. Unexpectedly, rare, totipotent-like stem cells have been identified in cultured ESC populations, suggesting the existence of a discrete molecular pathway that regulates the transition between totipotency and pluripotency in vitro. Here, we identify a single miRNA, miR-34a, whose deficiency in mouse pluripotent stem cells expands cell fate potential, giving rise to both embryonic and extra-embryonic lineages in vitro and in vivo. The expression profiles of the totipotent-like miR-34a-knockout murine pluripotent stem cells are characterized by a strong induction of MERVL endogenous retroviruses, a key molecular hallmark shared with totipotent mouse 2-cell blastomeres and totipotent-like mouse ESCs. In all three cell types, a subset of MERVL elements promotes the expression of specific isoforms of the proximal protein-coding genes. We demonstrate that miR-34a represses MERVL expression through transcriptional regulation, at least in part, by directly targeting the transcription factor GATA-binding protein 2 (Gata2). Since MERVL activation correlated precisely with the totipotent-like state, we hypothesized that the miR-34a/Gata2 pathway that regulates MERVL expression in ESCs/iPSCs also regulates the acquisition of totipotency in culture. Consistent with this hypothesis, gata2 knock-down in miR-34a-knockout mouse pluripotent stem cells not only reduced MERVL expression, but also abolished the expanded cell fate potential of these cells both in vitro and in vivo. Taken together, our findings not only provide key insights into the functional importance of miR-34a in restricting the totipotent cell fate potential of pluripotent stem cells, but also elucidate the underlying molecular basis by which miR-34a regulates the developmental potentials of ESCs/iPSCs.

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Relaxed 3D genome conformation facilitates the pluripotent to totipotent-like state transition in embryonic stem cells

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