Virology Faculty Member - Yang Shi

Yang Shi

Harvard Medical School
New Research Building, 854B
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-432-4318
Fax: 617-432-6687
Email: yang_shi@hms.harvard.edu



Histone methylation has been implicated in multiple biological processes including heterochromatin formation, X-inactivation, genomic imprinting and silencing of homeotic genes. Methylation occurs on both lysine (K) and arginine (R) residues. Multiple K residues on the tails of histone H3 and H4 have been shown to be sites for methylation. Methylation at these sites has been linked to both transcriptional activation and repression, as well as DNA damage response, demonstrating a widespread role for histone methylation in various aspects of chromatin biology. Lysine residues can be mono-, di-, or tri-methylated. These differentially methylated lysine residues may serve as docking sites for different effector proteins and/or platforms for chromatin modifiers including histone methylases, deacetylases or remodeling activities, which may result in potentially diverse functional outcomes. In sum, methylation at different lysine residues, degrees of methylation at the same lysine residue, as well as the locations of the methylated histone within a specific gene locus, can differentially impact chromatin structure and transcription, highlighting the complexity of histone methylation.

Unlike other histone modifications such as acetylation, methylation has long been considered a “permanent” modification. Our identification of the first histone demethylase LSD1 challenged this view, and suggested that histone methylation can also be dynamically regulated by both histone methylases and demethylases. LSD1 demethylates on di- and mono-methylated lysines. Thus it was unclear whether trimethylated lysines can be reversed by demethylases as well. Importantly, we have recently identified a subfamily of new histone demethylases that specialize in demethylating lysine trimethylation. Collectively these findings suggest that all three methylation states of the lysine residue (mono-, di- and trimethylation) can be reversed enzymatically. A current focus of the lab is to screen for additional demethylases using a candidate approach and to investigate the biology and mechanism of action of these histone demethylases in genetically tractable model organisms such as S. pombe and C. elegans. We are also interested in exploring potential disease connections of these newly identified chromatin regulators. Finally, we are using the assays established in the lab to search for potential DNA demethylases.

My lab also has a longstanding interest in the transcription factor Yin Yang 1 (YY1), which was initially isolated by us as a target of adenovirus E1A oncoproteins. The importance of YY1 is highlighted by the fact that E1A regulates the activity of YY1, and this regulation appears to be important for E1A to induce oncogenic transformation and to inhibit differentiation. Therefore, insights into YY1 function and mechanism of action in vivo are likely to enhance our understanding of cell growth control and tumorigenesis. Using a homologous recombination-based knock-out approach, we have recently identified an essential role for YY1 during early mouse embryogenesis. To study YY1 in later development, we have generated mice carrying a conditional allele of YY1 and are in the process of their analysis. Preliminary results suggest a crucial role for YY1 in B and T cell development. In addition, using a biochemical and proteomics approach, we have identified a link between YY1 and DNA damage and work is in progress to better define the role for YY1 in this important biological process.



Last Update: 10/22/2013



Publications

Liu, HF, Schmidt-Supprian, M., Shi, YJ., Hobeika, E., Barteneva, N., Reth, M., Skok, J., Rajewsky, K., and Shi, Y. (2007). Yin Yang 1 regulates the immunoglobulin heavy chain gene V to DJ recombination by controlling IgH locus contraction. Genes & Dev Vol 21:1179-89.

Iwase, S, Lan, F., Bayliss, P., de la Torre-Ubieta, L., Qi, H., Huarte, M., Whetstine, JR.,Bonni, A., Roberts, T., and Shi, Y. (2007). The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell Vol 128:1077-88.

Whetstine, JR., Nottke, A., Lan, F., Huarte, M., Smolikov, S., Chen, Z., Spooner, E., Li, E., Zhang, G.,Colaiacovo, M., and Shi, Y. (2006). Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell Vol 125:467-81.

Shi, YJ, Matson, C., Lan, F., Iwase, S., Baba, T. and Shi, Y. (2005). Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell Vol 19:857-864.

Shi, YJ., Lan, F., Matson, C., Mulligan, P., Whetstine, J.R., Cole, P.A., Casero, R.A. and Shi, Y. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell Vol 119:941-953.



© 2013 by the President and Fellows of Harvard College