Yang Shi, PhD
Professor
Department of Pathology, Harvard Medical School
Histone demethylation and gene regulation: gene expression; epigenetics; disease
Studies on lysine-specific demethylases and biochemical and functional aspects of histone demethylation.
Commercial Opportunities
By understanding the role of covalent chromatin alterations in gene regulation and disease, far-reaching implications for the development of therapeutics capable of ameliorating disease genotypes by restoring normal gene expression can be developed.
Dr. Shi’s laboratory research has led to significant advances in the field of chromatin control of gene expression. Histone modifications, such as the reversible methylation of lysine residues in the N-terminal tail region, represent a layer of cellular regulation that was previously unappreciated. This field has exploded in recent years, fueled in large part by the identification of the enzymatic processes that mediate covalent alterations of histones. By virtue of the finding that histone methylation is reversible via enzymatic removal of the methyl groups, a scientific sub-discipline was born that may lead to novel targets for drugs that can treat various diseases. The epigenetic ramifications are also significant because the stable inheritance of chromatin modifications, such as cytosine methylation, has already been correlated with genomic imprinting and X chromosome inactivation. Chromatin modifications participate in a complex set of regulatory pathways that can activate or mute gene expression, and most likely are prominent, when mis-regulated, in mediating multifactorial disorders such as cancer, neurological diseases, and diabetes.
Current Research Interests
Dr. Shi is:
- Studying the enzymology of histone demethylases that remove methyl groups from histones. These studies include addressing the mechanism of action, site and methyl group specificities for these important enzymes.
- Exploring of the effect of histone methylation/demethylation on structural parameters of chromatin; that is, how do cells “interpret” different histone modifications in terms of chromatin structure and gene regulation.
- Continuing efforts at isolating and identifying new histone modifying enzymes that are responsible for adding or removing methyl groups, and perform biochemical characterizations of these enzymes.
- Utilizing animal models to gain insights into the biology of histone demethylases.
- Studying the connection between the state of histone methylation and various diseases.
Research Expertise
Dr. Shi’s laboratory has been a leader in the field of chromatin structure as it relates to transcriptional control and epigenetics (that is, stable genetic traits passed on to progeny that are not correlated with changes in DNA sequence). With the lab’s discovery of the first lysine specific demethylase (LSD1) that acts upon lysine residues present in the N-terminal tails of histones, the lab revealed a key pathway of gene regulation that was previously unrecognized, and shed light on the “histone code”. The identification of an enzyme class that can liberate methyl moieties from histones, and thus modulate gene expression, has far-reaching ramifications for understanding basic mechanisms of gene regulation, as well as the etiology of various disease processes. LSD1 removes methyl groups from lysine-4 of histone H3, while other lysine demethylases target different lysine residues on histones. Moreover, there is strict specificity for these enzymes, in terms of the lysine residue targeted as well as the methylation state (that is, mono-, di-, or trimethylation).
Dr. Shi’s lab has recently begun to unravel the biochemical mechanisms that underlie demethylation, and identify cellular processes affected by histone demethylation. It was found that the protein BHC80 resides within the LSD1 protein complex and specifically recognizes and associates with unmethylated lysine 4 of histone H3. Functionally, suppression of BHC80 expression leads to transcriptional activation of genes regulated by LSD1-mediated histone demethylation, demonstrating a reciprocal loop involving BCH80 and LSD1 activities.
Other research has identified novel lysine-4 and lysine-27 trimethyl state-specific demethylases, and their roles in X-linked mental retardation, in HOX gene expression and consequently animal posterior development, respectively. These studies reinforce the idea that the methylation/demethylation status of histones has profound implications for gene expression, physiology and pathology.