ABSTRACT
In early mammalian development, cleavage stage blastomeres and inner cell mass (ICM) cells co-express embryonic and extra-embryonic transcriptional determinants. Using a protein-based double reporter we identify an embryonic stem cell (ESC) population that co-expresses the extra-embryonic factor GATA6 alongside the embryonic factor SOX2. Based on single cell transcriptomics, we find this population resembles the unsegregated ICM, exhibiting enhanced differentiation potential for endoderm while maintaining epiblast competence. To relate transcription factor binding in these cells to future fate, we describe a complete enhancer set in both ESCs and naive extra-embryonic endoderm stem cells and assess SOX2 and GATA6 binding at these elements in the ICM-like ESC sub-population. Both factors support cooperative recognition in these lineages, with GATA6 bound alongside SOX2 on a fraction of pluripotency enhancers and SOX2 alongside GATA6 more extensively on endoderm enhancers, suggesting that cooperative binding between these antagonistic factors both supports self-renewal and prepares progenitor cells for later differentiation.
Subject(s)
Gene Expression Regulation, Developmental , Transcription Factors , Animals , Cell Lineage/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Cell Differentiation/genetics , Germ Layers , Endoderm , Blastocyst , Mammals/metabolismABSTRACT
PURPOSE OF REVIEW: Global epigenetic reprogramming of the parental genomes after fertilization ensures the establishment of genome organization permissive for cell specialization and differentiation during development. In this review, we highlight selected, well-characterized relationships between epigenetic factors and transcriptional cell fate regulators during the initial stages of mouse development. RECENT FINDINGS: Blastomeres of the mouse embryo are characterized by atypical and dynamic histone modification arrangements, noncoding RNAs and DNA methylation profiles. Moreover, asymmetries in epigenomic patterning between embryonic cells arise as early as the first cleavage, with potentially instructive roles during the first lineage allocations in the mouse embryo. Although it is widely appreciated that transcription factors and developmental signaling pathways play a crucial role in cell fate specification at the onset of development, it is increasingly clear that their function is tightly connected to the underlying epigenetic status of the embryonic cells in which they act. SUMMARY: Findings on the interplay between genetic, epigenetic and environmental factors during reprogramming and differentiation in the embryo are crucial for understanding the molecular underpinnings of disease processes, particularly tumorigenesis, which is characterized by global epigenetic rewiring and progressive loss of cellular identity.
