From LSD1 to SMCX to TET and Beyond
Histone Demethylase Family and Impact on Histone Methylation Dynamics
Histone lysine methylation comes in many flavors, with mono-, di- and tri-methylation occurring at various residue positions. These key epigenetic modifications have a critical role in regulating chromatin state, and thereby modulating gene transcription. The seminal discovery of LSD1/KDM1A by Dr. Shi in 2004 illuminated the dynamic regulation of these marks, which were once thought to be permanent. Our lab was the first to characterized LSD2/KDM1B, the human homolog of LSD1, as a regulator of histone lysine methylation, and we have reported its novel function of regulating gene expression after the initiation of transcription. Importantly, our lab has also identified and characterized novel LSD cofactors, including CoREST and NPAC. Following the discoveries of LSD1 and LSD2, mono- or di- lysine 4 specific demethylases, we and others discovered the first tri- lysine 4 specific demethylase activity of SMCX. We linked the loss of SMCX demethylase activity to the impairment of REST-mediated neuronal gene regulation and provided significant insight into the mechanisms underlying the pathological development of SMCX-associated X-linked mental retardation . These findings have contributed significantly to the understanding of epigenetic regulation in cellular biology and opened a new chapter in the dynamics of histone regulation.
Our ongoing research aims to further our understanding of histone demethylation and its regulation, the mechanisms underlying their delicate dynamics, and the associated biological consequences. Our current projects include:
- Discovering novel histone demethylases and their cofactors
- Investigating how LSD1/ 2 and their respective cofactors regulate gene transcription and co-transcriptional events
- Studying the role of LSD1/2 and their cofactors in cancer and immunotherapy
- Exploring the role and mechanism of action of histone demethylases in neurological and psychological disorders
DNA Methylation and TET Proteins: Deciphering the DNA Demethylation Process
DNA methylation at the 5th position of cytosine (5-methylcytosine, 5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-methylcytosine can undergo further oxidation to 5-hydroxymethycytosine(5-hmC), 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC), a process mediated by the Ten-eleven translocation (TET) family proteins. Our lab was one of the first groups that identified TET1 as a DNA methylation hydroxylase and unveiled the intricate role of 5mC and 5hmC in stem cell biology. Our lab was also one of the first to characterize the putative tumor suppressive role of TET2 in cancer. We also determined the crucial role of TET3 in early eye and neural development. Furthermore, we were the first group to identify the loss of 5-hydroxymethylcytosine as a hallmark of cancer.
Our current projects include:
- Identifying novel regulators of the DNA methylation pathway and new mechanisms for DNA demethylation
- Exploring DNA methylation dynamics and how environmental insults deregulate this balance and result in human pathologies, such as Alzheimer’s disease and cancer
- Elucidating how the interaction between TET family proteins with other cellular factors impacts critical processes such as gene regulation and DNA demethylation
- Exploring the state of 5mC and TET-mediated oxidized products and identify epigenetic signatures associated with early and late onset Alzheimer’s disease and specific cancer types
- Investigating the mechanism by which DNA damaging insults such as ROS/NOS, anti-tumor drugs, and UV radiation, disrupt the cellular machinery that is responsible for maintaining the state of DNA methylation