Overview
Our group is interested in interrogating the impact of genetic mutations in epigenetic modifiers on the function of immune cells and immune-mediated diseases. We use various cutting-edge genetic and immunological tools as well as experimental model systems such as human pluripotent stem cells to address our questions.
Somatic mutations in epigenetic modifiers and immune cell dysfunction
DNA methylation is a heritable epigenetic mark. Methylation can change the activity of a DNA segment without changing the sequence. Somatic mutations in DNMT3A gene (encoding a writer of DNA methylation) and TET2 gene (encoding an eraser of DNA methylation) are remarkably common in blood stem cells of elderly individuals, estimated to affect more than 10% of adults over the age of 65, in a process referred to as clonal hematopoiesis. These mutations increase the risk of developing various diseases, most strikingly atherosclerosis, thereby nearly doubling the mortality rate of affected individuals. It is not understood how dysregulation of DNA methylation in blood stem cells leads to atherosclerosis and other clonal hematopoiesis-associated diseases. As blood stem cells give rise to immune cells, we hypothesize that these mutations modify the function of immune cells. We use genetically modified human pluripotent stem cells and immune cells derived from them to test our hypothesis.
Germline mutations in epigenetic modifiers and congenital growth syndrome
Our research focuses on the molecular mechanisms underlying overgrowth syndromes with intellectual disability (OGID), a rare genetic disorder caused by de novo germline mutations. OGID is characterized by excessive prenatal and postnatal height growth, macrocephaly, distinctive craniofacial features, and varying degrees of intellectual disability.
We investigate mutations involved in epigenetic regulation genes, such as EZH2, NSD1, and DNMT3A, which play crucial roles in chromatin modification, transcriptional regulation, and developmental processes, and whose hetero mutation are known to cause OGID. Mutations in these genes disrupt normal epigenetic programming, leading to altered gene expression patterns and abnormal cellular functions that underlie the clinical symptoms of OGID. However, the shared biological mechanisms remain unknown.
To investigate the effects and biological mechanisms of these epigenetic disruptions, we generate multiple human embryonic stem cell (hESC) lines with those genetic mutations using CRISPR-Cas9 genome editing technology. Using these mutant cell lines, we conduct comprehensive epigenetic, genomic, transcriptomic and cell biological analysis with state-of-the-art technologies to clarify how mutations in these epigenetic regulators lead to abnormal gene expression and ,ultimately, abnormal cellular phenotypes.
By integrating bioinformatics, molecular biology, and cell biology, we aim to provide novel insights into the pathogenesis of OGID and the role of epigenetic dysregulation in genetic disorders.
Gene expression regulation by DNA methylation and other epigenetic marks