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Transcriptional and Epigenetic Regulation of Totipotency in Mouse Early Embryos.

Periodic Reporting for period 2 - Totipotency (Transcriptional and Epigenetic Regulation of Totipotency in Mouse Early Embryos.)

Reporting period: 2018-02-01 to 2019-07-31

In mammals, fusion of two highly differentiated gametes gives rise to a totipotent zygote capable of developing into a whole organism. It coincides with translation and degradation of maternally provided transcripts, initiation of global transcription called zygotic genome activation (ZGA), and “epigenetic reprogramming” of germline chromatin states into an embryonic state. The molecular mechanisms underlying this exquisite reprogramming of cell fate are barely understood.
The research project has the goal to identify and characterize transcription factors and chromatin regulators which regulate ZGA in early mouse embryos. We utilize novel and highly sensitive genomic approaches to measure nascent transcription and determine open and modified chromatin landscapes in oocytes and early embryos, wild-type and conditionally deficient for major epigenetic modifiers. We apply computational approaches to identify candidate TFs and histone modifiers controlling ZGA. We use molecular and developmental biology approaches, combined with live-imaging, to interrogate the function of TFs for ZGA. We further investigate the role of chromatin remodeling during spermatogenesis for gene regulation during embryogenesis. By transferring nuclei of immature and mature male germ cells into oocytes, we interrogate the relevance of nucleosome eviction during spermatogenesis, as a possibly epigenetic reprogramming process, for defining embryonic competence.
The project provides a crucial contribution to dissecting molecular mechanisms underlying acquisition of totipotency in mouse embryos. It will deliver basic insights into mechanisms and significance of intergenerational epigenetic inheritance versus reprogramming of germ line chromatin states in early embryos. The obtained findings will inspire basic research on the use of Assisted Reproductive Technologies in human reproductive medicine for treating human male sterility.
We have made significant progress in understanding the role of chromatin states inherited from female and male germ cells in regulating gene expression in early embryos. Intergenerational transmission of certain chromatin states is instructive for gene expression activity in early embryos in a parental allele specific manner. Loss or gain of transmission of such chromatin marking impairs proper gene expression in and development of pre-implantation embryos (Bammer, Ozonov et al., in prep; Kitazawa et al., in prep; Liu et al., in prep). Moreover, we elucidated a role of the Polycomb
Revealing mechanistic principles underlying zygotic genome activation in mouse pre-implantation embryos will contribute to the general understanding of the role of transcription factors and chromatin states in gene regulation. Allele specific difference in chromatin states will enable dissection of the contribution of paternal and maternal chromatin in instructing gene expression states during development.