My interests lie in understanding epigenetic regulation of mammalian genomes during the earliest stages of mammalian development. Although brief in time, preimplantation development is an extremely dynamic period during which major epigenetic remodeling occurs and the very first cell fate decisions are made. These key biological processes require global, yet exquisitely precise chromatin remodeling and differential treatment of identical DNA sequence. We utilize various RNAi and knock-out approaches towards identification of genes that regulate these early epigenetic decisions that occur during oogenesis and preimplantation development.
The Knockout Mouse Project
The goal of this project is to characterize mutant mice generated by the Knock-out Mouse Consortium (KOMP2) that have lethal phenotypes occurring before to E9.5. Thus far we have nearly 100 distinct KOMP2 knockout lines successfully pass through our phenotyping pipeline. We will provide date to the IMPC to be incorporated into the international effort to functionally annotate the mammalian genome. This data set will drastically increase the number of documented early phenotypes and we believe it is the largest consistent characterization of early phenotypes on record.
This primary screen will provide baseline phenotypic data for many novel knockouts. To our knowledge this is the first systematic study of early lethal knockouts conducted using similar mutation strategies on the same genetic background (C57Bl/6JN). This large-scale analysis allows us to draw conclusions regarding developmental constraints during mammalian development and will provide a road map to early phenotypic characterization.
Thus far we have found approximately equal distribution of phenotypes – approximately half gastrulation/perigastrulation phenotypes and the other half with preimplantation/implantation phenotypes. This is not unexpected as one of our original goals was to determine if there are specific milestones during development at which embryos would arrest or present phenotypic abnormalities (as opposed to a gradient of phenotypes across all time points).
Genomic imprinting is an epigenetic mechanism resulting in differential transcriptional activity between the two parental alleles. It is well established that differential chromatin structure accompanies this parent of origin gene expression. More specifically, DNA hypo/hyper-methylation, and core histone modifications (acetylation/methylation) differ between the active and silent alleles. Disruption of any one of these chromatin modifications may result in loss of imprinting at particular loci, making imprinted genes sensitive “reporters” of epigenetic regulatory mechanisms. Our group is engaged in an RNAi based screen to identify novel epigenetic regulatory genes. We screen for loss of imprinting, defects in trophoblast/ICM differentiation, as well as developmental arrest and morphological abnormalities all within the same preimplantation embryos.
Learn more at www.vasci.umass.edu/research-faculty/jesse-mager
- PhD University of North Carolina
- Postdoctoral Training: University of Pennsylvania