Epigenetic Control of Development: Establishment and function of placenta-specific DNA methylation patterns

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My central research program examines the molecular processes that govern development of the placenta. My particular research focus is on how genes are regulated through instructive layers of information that are collectively known as the epigenome. I am aiming to understand how epigenetic modifications drive and reinforce cell fate decisions by establishing cell type-specific transcriptional networks that are of critical importance for developmental progression, ultimately ensuring reproductive success. DNA methylation is an epigenetic modification that is indispensable for embryonic development. The genomic distribution of DNA methylation in a cell lineage- and cell type-specific manner is key to reinforcing cell fate decisions, thereby ensuring stable differentiation. The placental trophoblast lineage is characterized by a unique DNA methylation profile that is highly distinct from that of embryonic cells. The establishment of this specific pattern is of crucial importance for trophoblast differentiation and normal placentation. Thus, mouse mutants that are defective in various components of the DNA methylation machinery or that lack specific methylation marks die early during development with severe placental abnormalities. Despite the pivotal importance of DNA methylation for placental development, it remains unknown how this epigenetic mark is targeted to specific sites in the genome to establish the distinct trophoblast-specific epigenomic landscape. This fundamental mechanistic question is the focus of my NSERC program. Since the DNA methylation machinery does not exhibit sequence-specificity by itself, the central hypothesis of this work is that a particular collection of DNA binding proteins unique to the trophoblast lineage confers the targeting of the DNA methylation machinery to particular sequence elements. The factors that combine sequence-specific DNA binding affinity with the attraction of DNA methylation components are called Kruppel-associated box zinc finger proteins (KRAB-ZFPs). This program of work is aimed at identifying critical KRAB-ZFPs that collectively establish the trophoblast methylome. The specific objectives are to: Aim #1: Identify and characterize trophoblast-enriched KRAB-ZFPs Aim #2: Establish the genomic occupancy profile of trophoblast KRAB-ZFPs Aim #3: Determine the capacity of KRAB-ZFPs to establish trophoblast-specific DNA methylation patterns Aim #4: Evaluate the impact of KRAB-ZFP ablation on trophoblast development Overall, this study will set milestones for our mechanistic understanding of how placental DNA methylation patterns are established, which is of fundamental importance for development and reproduction. Our HQP will learn cutting-edge stem cell and CRISPR gene editing techniques, bioinformatics analysis methods and epigenomic profiling technology, which will position them as leaders in Canada's natural sciences sector.