Genomic imprinting is a classical epigenetic phenomenon that restricts gene expression in a parental origin manner. This phenomenon was first noticed in pronuclear transfer experiments where embryos with androgenetic (AG: solely paternally diploid genomes) or gynogenetic (GG: solely maternally diploid genomes) were unable to develop normally, indicating allelic epigenetic imprints are required for normal development. Imprinted gene expression is controlled by cis-regulatory elements, termed imprinting control regions (ICRs), which are DNA methylated in a parental-specific manner. Defects in imprinting have been associated with several human syndromes and diseases such as Prader-Willi and Angelman syndromes. The fact that many imprinting-related syndromes are caused by loss function of the expressed allele raises the possibility of therapeutic intervention through epigenetic activation of the silenced functional allele. We have recently discovered a novel H3K27me3-mediated DNA methylation-independent imprinting mechanism. Build on this new finding, this proposal plan to use a combination of embryo biology, computational biology and synthetic biology approaches to understand this new imprinting mechanism. First, I will identify ICRs of the newly identified H3K27me3-mediated imprinting genes using the expertise of Dr. Yi Zhang lab (micro injection, pronuclear transfer and low-input DNase-seq) and Dr. Guo-Cheng Yuan lab (computational biology). Second, a CRISPR-Cas9-based epigenomic editing technique developed by Dr. Feng Zhang lab will be used to functionally characterize the ICRs. Lastly, I will take advantage of the new technologies and computational pipelines developed learned during my mentored phase to comprehensively map the cell type specific imprinting in placenta, one of the most important organ for imprinting genes function. This career development award will allow me to develop new technologies as well as further strengthen my computational skills. Combining these new skills with my previous training in epigenetics and genomics will better prepare me as an independent investigator. The excellent research environment in Boston Children's Hospital and Harvard Medical School will greatly facilitate my research and career development during mentored phase to transit to an independent academic position. Collectively, the proposed study will pave the road to launch my future research that aim at elucidating the rules governing dynamic regulation of H3K27me3-mediated genomic imprinting in normal and human disease states.
Some of imprinting human disorders caused by one copy of a gene inherited from parents is expressed but mutated while another copy is wild type but epigenetically silenced. One way to treat these disorders might be to turn that gene on by epigenetic perturbation, meaning without change to the DNA sequences. The proposed study is to investigate the fundamental principle of newly discovered imprinting mechanisms, using a combination of high-throughput genomics technologies and novel synthetic biology tools, which eventually may lead to novel therapeutic strategies.
