Eukaryotic cells need to deal with the biophysical constrains of packaging 2 meters of DNA inside a tiny nucleus (2 -10 microns) and retain the ability to access both its coding and non-coding elements to precisely orchestrate gene expression programs. Research over the past decade has started to elucidate the mechanisms through which DNA condensation and organization in the nucleus are achieved. These suggest that these processes are tightly controlled and are themselves critical components of gene regulation. Our long-term goal is understand how these processes occur in vivo and how their regulation dictates cell identity and cell fate decisions in mammals. To do so, our research program combines the robustness of mouse genome editing and genetics with cutting-edge sequencing-based genomic techniques such as ATAC-seq, ChIP-seq and Hi-C, as well as live imaging approaches. We believe the early mouse embryo is an ideal model system to ask how nuclear architecture is regulated in the context of an organism and how it impacts cell behavior and identity: First, fertilization is the ultimate reprograming experiment where two highly differentiated cells (oocyte and sperm) fuse to form a zygote with totipotent potential. This involves a massive rearrangement of epigenetic modifications both at the level of the DNA and of the histones, and the activity of several transcriptional regulators. Our studies aim to understand how 3D chromatin structures are established during this period, and how this impacts future developmental decisions. Second, following fertilization and within a few cell divisions, the first cell-lineages are established and different gene-expression programs put in action. In mammals this results in the formation of the blastocyst, a structure that contains three different cell types, each with a defined differentiation potential. The trophectoderm will be responsible for forming the placenta, the primitive endoderm will lead to the yolk sac and the epiblast will give rise to all remaining embryonic tissues. We will build on decades of lineage-fate experiments and precisely characterized signaling pathways known to regulate early mouse development to understand the contribution of nuclear organization to gene regulation during these early cell fate decisions. Finally, we are interested in understanding not only how DNA organization impacts cell behavior, and ultimately animal development and health but also the mechanisms through which DNA folding itself is established and regulated, and which proteins are involved in these processes. To broadly ask these questions, we will employ a number of high-throughput technologies we have established in the lab in combination with genome-wide CRISPR screens. Ultimately, candidates identified this way will be fully characterized in vivo to stringently determine their impact in gene regulation during mammalian development.

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U.S. National Inst/Child Hlth/Human Dev
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Oksuz, Ozgur; Narendra, Varun; Lee, Chul-Hwan et al. (2018) Capturing the Onset of PRC2-Mediated Repressive Domain Formation. Mol Cell 70:1149-1162.e5