Epigenetic mechanisms and gene regulation in development and diseases
In eukaryotic cells genetic information is encoded in DNA templates that are wrapped into chromatin containing both DNA and histones. Epigenetic modifications of chromatin, particularly DNA methylation and covalent histone modifications, play a critical role in regulating gene transcription in which transcription factors bind to specific regulatory sequences and extract genetic information from DNA templates. Tight regulation of these processes by tissue-specific transcription factors acting in concert with epigenetic factors is essential for cell fate determination and lineage specification during normal development.
My previous studies discovered that the histone demethylase Kdm2b binds to the gene regulatory elements called CpG islands through its CxxC-zinc finger DNA binding domain. It further modifies the local chromatin structure by recruiting Polycomb Repressive Complex 1 (PRC1). Functionally, it is important in maintaining murine embryonic stem cells by repressing spontaneous lineage gene activation. The Kdm2b/PRC1 complex-mediated gene repression was also demonstrated to be important in repressing Ink4-Arf locus that plays a critical role in cellular senescence and tumorigenesis.
Building on these findings, my lab will use biochemical assays, molecular biology, genomics analysis, genomic editing, and animal models to investigate some fundamental questions related to epigenetic regulation and gene expression during normal development as well as in diseases. The studies will be focused on:
(1) dynamic epigenetic modifications at gene regulatory elements during lineage specification and cell fate determination;
(2) molecular mechanisms involved in antagonizing the Polycomb-mediated repression during lineage-specific gene activation;
(3) functional role of epigenetic mechanisms in maintenance of adult stem cells and tissue regeneration;
(4) functional role of epigenetic mechanisms in cancer stem cells and tumorigenesis.
The long-term goal of these studies is not only to advance our understanding of basic epigenetic mechanisms in gene regulation, but also to provide critical insights into developing new therapeutic approaches to treat human diseases.