The EPIC unit, results from the transformation of Pablo Navarro’s young group (Pasteur G5; 2013-2018) into a full unit in January 2019. The G5 made several contributions to the fields of gene regulation, chromatin biology and pluripotent stem cell self-renewal. Indeed, a key observation made in pluripotent embryonic stem (ES) cells is their capacity to self-renew even when key epigenetic regulators are inactivated; a phenomenon that we quoted as the “epigenetic paradox of pluripotency”. This is so because in contrast to other cell types, ES cells strictly depend on the activity of transcription factors (TFs). Yet, self-renewal imposes transiting through replication and mitosis, which alter chromatin states and invalidate TF activity. These considerations lead to several questions: 1/ are the repressive histone modifications found at differentiation genes truly epigenetic in ES cells? If not, how then do ES cells maintain these marks and other chromatin properties as they self-renew? What the precise role of TFs is in the control of the chromatin, particularly during replication and mitosis?
From this conceptual ground, we discovered two important regulatory principles. First, that repressive histone methylation is strictly dependent on TFs, such as Nanog, and signaling pathways centered on ERK and LIF (Nature Communications). Second, that some TFs such as Esrrb, but also CTCF, display the outstanding capacity to survive replication and mitosis: in contrast to other TFs, they both rebind rapidly after the passage of the replication fork and maintain their binding capacity during mitosis, when the chromosomes fully condense. Through their binding, Esrrb/CTCF maintain nucleosome order, whereas at regions losing TF binding the nucleosomes take over and mask TF binding motifs. Hence, Esrrb and CTCF confer nucleosome resiliency to replication and mitosis, possibly forstering the reassembly of regulatory complexes in nascent chromatin fibers and in daughter cells (Nature Cell Biology, Genome Research and eLife). Overall, we pioneered the field of mitotic bookmarking factors in ES cells, delivered the first mechanistic basis of their function, and extended their activity to replication, hence producing a new concept, that of “resilient TFs”. Together, these studies enabled Pablo Navarro to receive the Schlumber Foundation price ( 2015), a consolidator ERC (2017) and the Ligue Contre le Cancer label (2018).
Moreover, the group of Michel Cohen-Tannoudji, one of the most recognized French early mouse embryologists, in now part of EPIC. His group has made key contributions to understand the establishment of the pluripotent epiblast and the primitive endoderm in vivo, including the identification of strict temporal windows of cell responsiveness to inductive cues (Scientific Reports) and intracellular pathways required for lineage stability after specification (Stem Cells). This strategic restructuration, which will enable us to fruitfully combine our complementary expertises, is central to the unfolding of our scientific agenda.
Together, we will address some of the most critical questions in Epigenetics and Developmental Biology: is epigenetic regulation the only mechanism conveying regulatory information to daughter cells? Can the action of transcription factors and long non-coding RNAs be by itself epigenetic? Are histone modifications inherently epigenetic or do they require the constant input of upstream regulators? Are these mechanisms functionally important during normal and pathological processes involving cell proliferation? Therefore, we will explore how cell identity is specified and maintained during the proliferative processes characterizing stem cell self-renewal and differentiation, early mouse development and cancer biology.
This ambitious scientific goal, which requires diverse expertises in molecular, cellular, developmental and computational biology, will be supported by both internal (Pasteur, CNRS, Revive labex) and already secured external grants (Consolidator ERC 2018-2023 and Ligue Contre le Cancer 2018-2023).
