Epigenetic mechanisms in neural development and stem cell regulation
Our current research focuses on understanding epigenetic mechanisms that regulate neural stem cell differentiation, adult brain function, and somatic cell reprogramming. We utilize molecular and genetic approaches to investigating how DNA cytosine methylation and its associated components, which include methyl-CpG binding proteins and histone modification enzymes, regulate gene expression, cell differentiation and reprogramming, and neural plasticity in mammalian systems.
1).DNA methylation in neural development and function:
Abnormal DNA methylation has been associated with several human mental retardation disorders, including fragile-X, ICF (immunodeficiency, centromere instability, and facial anomaly), and Rett Syndromes. To study the methylation function in the brain, we have used the Cre/loxP conditional gene knockout method to produce transgenic mice that are deficient of the DNA methyltransferase I (Dnmt1) exclusively in the central nervous system (CNS). Dnmt1 deficiency results in DNA hypomethylation in CNS precursor cells and their progeny neuronal and glial cells. We found that DNA hypomethylation affects neuronal and astroglial differentiation as well as postnatal neuronal survival and maturation in the CNS. We are currently defining the molecular mechanism by which DNA hypomethylation alters neuronal gene expression (Science 302: 890-893), cell survival, and lineage-differentiation in the CNS (Human Molecular Genetics 18:2875-2888).
2).Epigenetic mechanisms underlying stem cell regulation, reprogramming, and human diseases
The recent breakthrough of reprogramming somatic cells into induced pluripotent stem cells (iPSCs) also provides us with a unique opportunity to model human genetic disorders in stem cells. One of the focuses in our lab is to establish human iPSCs carrying genetic mutations leading to human diseases such as Fragile-X and ICF Syndrome. These human disease-specific iPSCs will be powerful model systems to dissect molecular and epigenetic mechanisms underlying these human diseases. Our second focus is to study how genome-wide DNA methylation is regulated in cell reprogramming.
Both embryonic stem (ES) cells and induced pluripotent stem cells (iPSCs) can be induced to differentiate into multiple somatic cell lineages in vitro. However, mechanisms underlying directed differentiation of pluripotent stem cells are poorly understood. To examine whether cell lineage-specific differentiation of stem cells is regulated by epigenetic factors such as DNA methylation and histone modifications, we have established a culture system to induce sequential neural lineage differentiation with both mouse and human ESCs and iPSCs. Understanding epigenetic mechanisms underlying stem cell differentiation allows us to devise and standardize methods to convert pluripotent stem cells into neural precursor cells and specific types of neurons for neural repair.