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Investigating embryonic development at the time of implantation using embryos and ES cells

Periodic Reporting for period 1 - embryonic rosettes (Investigating embryonic development at the time of implantation using embryos and ES cells)

Reporting period: 2016-02-01 to 2018-01-31

Nuclear organization during the pre-implantation development of the mouse embryo displays features necessary for the reprogramming of chromatin. These involve histone modifications, nuclear repositioning, and the reorganization of chromatin associated with activation of specific genes. These changes occur in the embryo after fertilization and are necessary for the establishment of the three lineages of the blastocyst: the pluripotent epiblast (EPI) that gives rise to the future body of the animal and which together with extra-embryonic primitive endoderm (PE) is derived from the inner-cell-mass (ICM), and the trophectoderm (TE), the other extra-embryonic tissue that forms the placenta. It has been shown that differences in epigenetic modification between early blastomeres are linked to their fate. Therefore, cells with increased histone H3 arginine 26 methylation (H3R26me2), considered as an activating mark, show higher expression of a subset of pluripotency genes that include Nanog, Sox2 or Oct4, and are destined to contribute to embryonic rather than extra-embryonic tissues . Differential levels of histone H3R26me2 between 4-cell blastomeres are mediated by the heterogeneous activity of the histone coactivator associated arginine methyltransferase 1 (CARM1). However, nuclear organization has never been carefully examined during early mammalian development at the stages leading to establishment of ICM and TE.
Obtained results show that CARM1 accumulates in nuclear granules in the early mouse embryo, the majority corresponding to paraspeckles. The paraspeckle components are required for CARM1’s association with paraspeckles and for H3R26 methylation. Conversely, CARM1 also influences paraspeckle organization. Depletion of Neat1 or p54nrb results in arrest at the morula stage with elevated expression of transcription factor Cdx2, promoting differentiation into the extra-embryonic lineage indicating that paraspeckles act upstream of CARM1.
We expect that dissemination of the findings to other key groups (academic and clinical/industrial) within Europe, and beyond, will occur through scientific publications in peer-reviewed journals, the network of collaborators within and outside of Cambridge, e.g. through conference presentations.
The project will enhance the circulation and transfer of scientific knowledge through conference attendance and publication of research results in peer-reviewed journals, networking and collaboration, and will improve public scientific awareness through impact activities. The greatest academic benefit will be in the highly active and competitive research fields of early embryonic development of model organisms such as mouse as well as stem cell biology.
Our work will generate several primary and secondary datasets that can have value to the larger community (e.g. time-lapse imaging movies of embryo development; deep sequencing data on the transcriptomes of different cell types or different subcellular compartments throughout early embryogenesis; functional studies of differentially expressed genes).
CARM1 accumulates in nuclear granules in the 4-cell stage mouse embryo