Basic Epigenetic Discoveries
A major source of epigenetic information in a cell is stored in the form of chemical modifications within its DNA, RNA and histone proteins. Many of these modifications are dynamically created (written), recognized (read), and removed (erased) throughout the life cycle of eukaryotic organisms. A central focus of our research is the discovery and investigation of genes that coordinately shape and interpret this epigenetic landscape, which impact biological processes. With the discovery of the first histone methyl eraser, LSD1, in 2004, our group demonstrated that histone methylation is dynamically regulated, which overturned the long-held dogma that such modifications were static and irreversible. We have also identified novel readers, including those that specifically recognize unmodified lysine and arginine and suggests that the unmodified states are not simply a ground neutral state of epigenetic information but rather likely code for epigenetic information as modified states. Our chromatin-based studies have expanded to include RNA modifications. Many RNA species are decorated with chemical modifications that regulate their function. With the improvement of detection and mapping technologies that allow us to study the so-called “epi-transcriptome”, we have recently identified several new RNA methyltransferases and are now in the position to address the function of the modifications that these enzymes mediate as well as the underlying mechanisms. In many ways this exciting field parallels the early days of chromatin biochemistry and biology, i.e., the nature and function of RNA modifications, as well as the enzymes responsible for writing, erasing and reading them, are just beginning to be understood. Finally, our lab has also expanded to explore the role of epigenetic modifications in the context of human diseases, including cancers and neurological disorders (detailed below). We believe the synergy of discovering new epigenetic regulators, characterizing their modes of action, and exploring their physiological relevance to disease will yield novel and fruitful insights to advance the broader enterprise of precision medicine.
I. RNA modifications
We study RNA m6Am methylation as well as m6A methylation events that occur on transcripts other than mRNAs. Our recent studies led to the discovery of PCIF1, an RNAPII-binding protein, as the enzyme that mediates m6Am methylation of the Cap-adjacent adenosine. We have also identified enzymes that mediate rRNA m6A methylation. With these enzymes in hand, we are now in the position to investigate the biological function and mechanism of action of these modifications.
II. Chromatin and Cancer
1). Enabling immune checkpoint blockade therapy by manipulating epigenetic regulators
Cancer immunotherapy, particularly PD-(L)1-directed checkpoint blockade therapy, has revolutionized cancer treatment. However, a majority of cancer patients show only partial or no response, or temporary responses to PD-(L)1-targeted therapy. Thus, there is a clear unmet clinical need to extend the benefits to non-responders and to achieve a long-lasting therapeutic effect. Our recent study using LSD1 as an example suggests that epigenetic regulators play critical roles in modulating antitumor immunity and tumor responses to immunotherapy. We are interested in uncovering a network of epigenetic regulators and action of mechanisms that impact tumor response to host immunity and immunotherapy. We are also interested in conducting proof-of-concept study on new combination strategy, in which epigenetic regulators are targeted for overcoming tumor resistance to immunotherapy.
2). Pediatric Brain Cancer
Sequencing of pediatric high-grade glioma (pHGG) samples has recently identified mutations in genes encoding the histone proteins. H3K27M and H3G34R mutations observed in diffuse intrinsic pontine gliomas (DIPG) and non-brainstem high grade gliomas, respectively are localized to the histone tail region that is subject to extensive covalent modification, suggesting that these mutations might disrupt chromatin organization and function. We have conducted chromatin-focused CRISPR/Cas9 and chemical screens using primary, patient pHGG cell lines harboring histone mutations in order to identify epigenetic factors necessary for the growth and survival of pHGG cells. We are also performing mechanistic studies to follow-up on “hits” from these screens to determine if and how various chromatin regulators contribute to changes in pHGG chromatin structure, histone modification and gene expression. Ultimately, insights gained from these studies aimed at revealing epigenetic vulnerabilities in H3K27M and H3G34R mutant tumors may inform the development of more effective treatment strategies for children with brain cancer.
3). Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a deadly cancer in need of more effective treatments. A general property of AMLs is defective differentiation, where the self-renewing leukemic stem cell undergoes limited differentiation to generate the leukemic blast, an immature form of white blood cell incapable of further development into the mature myeloid effector cells. Studies from our lab and others found that inhibition of the lysine demethylase LSD1 partially overcomes the differentiation barrier in AMLs and promotes committed maturation and programmed cell death of leukemic cells. We have identified numerous specific metabolic pathways that, when targeted in tandem with LSD1 inhibition, enhance the efficiency of leukemic differentiation. We are currently exploring the mechanisms and clinical relevance of such combinatorial chromatin/metabolic drug strategies as novel safer treatment options for AML.
III. Chromatin and neurological disorders
We are studying X-linked intellectual disability using iPS cells containing mutations in the histone H3K4me2/3-specific demethylase KDM5C together with isogenic control cell lines to define mechanisms underlying intellectual disability. In parallel, we are also investigating the role of KDM5C in brain development using the knockout mice.