Division of Newborn Medicine, Dept of Medicine
Children's Hospital Boston
Department of Pathology,
Harvard Medical School
Enders Building, 9th Floor
300 Longwood Ave.
Boston, MA 02115
Tel: (617) 432-4318 (office) 432-0051/2261 (lab)
Fax: (617) 432-6687
7 postdoctoral fellows, 3 graduate students
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 (mono-, di, and tri-methylation). Methylation at these sites has been linked to transcriptional activation and repression, as well as DNA damage response, indicating a widespread role for histone methylation in various aspects of chromatin biology. Unlike other histone modifications such as acetylation, methylation has long been considered a “permanent” modification. Our identification of the first histone demethylase LSD1 disproved this dogma, and suggested that histone methylation is dynamically regulated by both histone methylases and demethylases. Importantly, we have recently identified another large family of new histone demethylases (JmjC) 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. Our findings firmly established the notion that histone methylation is dynamically regulated by both histone methylases and demethylases. We are currently addressing the issues of mechanisms and biology of these newly identified histone demethylases in genetically tractable model organisms such as S. pombe, C. elegans and zebrafish. We are also exploring potential disease connections of these newly identified chromatin regulators. Finally, we are continuing our screens for new histone demethylases and are also 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). The importance of YY1 is highlighted by the fact that the viral oncoprotein E1A regulates the activity of YY1, and this regulation appears to be important for E1A to induce oncogenic transformation and to inhibit differentiation. Thus, insights into YY1 function and mechanism of action in vivo are likely to enhance our understanding of cell growth control and tumorigenesis. We have generated mice carrying a conditional allele of YY1. Our investigation identified a crucial role for YY1 in multiple stages of B cell development. In early B cell development, YY1 appears to be necessary for V to DJ recombination by regulating the IgH locus contraction, implicating a potential role for YY1 in facilitating communications among non-contiguous DNA elements. Using a biochemical and proteomics approach, we have also identified a link between YY1 and DNA damage. Further investigations of YY1 in these processes will provide new and important insights into fundamental biological processes in mammals.
Shi, YJ., Lan, F., Matson, C., Mulligan, P., Whetstine, JR., Cole, PA., Casero, RA. and Shi, Y. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell Vol 119:941-953.
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.
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, 128:1077-88.
Qi, HH*, Sarkissian, M.*, Hu, GQ., Wang Z., Bhattacharjee, A., Gordon, DB., Gonzales, M., Lan, F., Ongushaha, PP., Huarte, M., Yaghi, NK., Lim, S., Garcia B., Brizuela, L., Zhao, KJ., Roberts, TM+, and Shi, Y+. (2010). Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature, Vol 466:503-7.
BBS webpage updated 6/14/2010