Epigenetic modifications, including DNA methylation and histone modifications, play crucial roles in regulating chromatin structure and gene expression. Over the last two decades, great progress has been made in identifying the enzymes responsible for adding and erasing these modifications. However, the biological functions of most epigenetic modifiers remain poorly understood.
Our laboratory is interested in unraveling epigenetic mechanisms in health and disease. We use genetic, biochemical, and molecular approaches to investigate the roles of epigenetic modifiers, particularly those involved in DNA methylation and histone lysine methylation, in mammalian development, physiology, and various diseases.
Our current work focuses on the following areas:
- Crosstalk between DNA methylation and histone modifications
- Epigenetic modifiers in development and diseases
- Epigenetic regulation of stem cell behaviors and functions
Crosstalk between DNA methylation and histone modifications.
Various epigenetic mechanisms act cooperatively and coordinately in the regulation of chromatin structure and gene expression. Genome-wide studies have revealed that the distribution of DNA methylation marks correlates with enrichment or depletion of specific histone modifications. Our work focuses on the interplays between DNA methylation and histone modifications in developmental processes and cancer. For example, we recently demonstrated that KDM1B (also known as LSD2 and AOF1), a lysine demethylase that specifically removes mono- and di-methyl marks at lysine 4 of histone H3 (H3K4me1/me2), is required for setting up DNA methylation marks in imprinted loci during oogenesis. Our results provided the first genetic evidence for the involvement of histone lysine methylation in the regulation of genomic imprinting.
The image to the right shows a model for the establishment of genomic imprints during gametogenesis. We propose that the erasure of H3K4 methyl marks (by KDM1B and perhaps other H3K4 KDMs) is a prerequisite for de novo DNA methylation (by the DNMT3A-DNMT3L complex) in imprinting control regions in germ cells.
Epigenetic modifiers in development and diseases.
Epigenetic states are relatively stable in somatic cells, but undergo drastic changes (epigenetic reprogramming) during gametogenesis and early embryogenesis. Genetic alterations of epigenetic modifiers are associated with developmental disorders and cancer. For instance, DNMT3B mutations cause ICF (Immunodeficiency, Centromeric instability, and Facial anomalies) syndrome, and DNMT3A mutations are frequently observed in hematologic malignancies. We are interested in determining the major epigenetic modifiers that are involved in epigenetic reprogramming events and in understanding the mechanisms by which mutations of epigenetic regulators lead to diseases. For example, we recently showed that the H3K4 demethylase LSD1 (aka KDM1A and AOF2) and the H3K9 methyltransferase SETDB1 (aka ESET and KMT1E) are critical regulators of oocyte meiotic progression.
The image to the right shows meiotic defects and fragmentation of LSD1-deficient ooyctes.
Epigenetic regulation of stem cell behaviors and functions.
Stem cells are characterized by their abilities to replicate themselves (self-renewal) and give rise to multiple cell types (differentiation). The totipotent zygote (fertilized egg) is capable of differentiating to both embryonic and extraembryonic lineages. The pluripotent ICM (inner cell mass) cells of the blastocyst-stage embryo, as well as ES cells (originating from the ICM), have the capacity to differentiate to all cell types except those in the placenta. The multipotent adult stem cells can give rise to several tissue-specific cell types. We are investigating the roles of enzymes involved in DNA methylation and histone modifications in the maintenance of ES cell pluripotency and differentiation, as well as adult stem cell functions including tissue regeneration and repair.
The image to the right shows the results of genetic lineage tracing experiments, which demonstrate that SETDB1-expressing cells at the bottom of intestinal crypts are intestinal stem cells capable of giving rise to all cell types of the intestinal epithelium.