Mamta V. Tahiliani

Assistant Professor, Skirball Institute of Biomolecular Medicine, Developmental Genetics. Department of Biochemistry and Molecular Pharmacology

Ph.D., 2009 Harvard Medical School

Keywords: Epigenetics, TET, Cancer, Stem Cells, DNA methylation



Contact Information: 

Skirball Institute of Biomolecular Medicine
540 First Avenue 4th floor, Lab 4
New York, N.Y. 10016
Office Tel: (212) 263-2854
Lab Tel: (646) 501-6955
Fax: (212) 263-7760

Administrative Contact:

Dolly Chan
Tel: (212) 263-7595

Epigenetic Modifications of DNA and Regulation of the Genome

Proper regulation of DNA methylation patterns is essential for embryonic development. DNA methylation is very dynamic during embryogenesis and is vital for parental imprinting, X inactivation, silencing of endogenous retroviruses as well as the regulation of genomic stability. De novo methylation and demethylation also occur in somatic cells during differentiation, tumorigenesis and aging. In contrast to the established relation between DNA methylation, DNA methyltransferases and gene silencing, the enzymes and processes regulating DNA demethylation are not well understood.

We recently discovered that the leukemia-associated TET (TET1/2/3) family of enzymes convert 5-methylcytosine (5mC) to the novel base 5-hydroxymethylcytosine (5hmC). Wealso found that 5hmC can be detected in the genome of mouse ES cells, and that both TET1, TET2 and 5hmC levels decline when ES cells are differentiated. These results suggest that 5hmC is a normal constituent of mammalian DNA, and identify TET1 as an enzyme with a potential role in epigenetic regulation through modification of 5mC. This discovery raised the exciting possibility that 5hmC is an intermediate in the long sought DNA demethylation pathway. Consistent with this hypothesis, we and others have since shown that cancer-associated mutations in TET2 impair itscatalytic activity leading to diminished levels of 5hmC and hypermethylation of promoters. This study described a new class of enzymes that catalyze a new modification of DNA and alters our perception of how DNA methylation status may be regulated in cells. The description of the regulated conversion of 5mC to 5hmC raises an enormous number of new questions that are of pressing importance. The immediate goal of our laboratory is to integrate 5hmC into known pathways of 5mC metabolism and to determine how 5hmC exerts its influence on the genome with the ultimate goal of understanding the role that 5mC and hmC play in genomic stability.

Selected Publications:

Pastor WA, Pape UJ, Huang Y, Henderson HR, Lister R, Ko M, McLoughlin EM, Brudno Y, Mahapatra S, Kapranov P, Tahiliani M, Daley GQ, Liu XS, Ecker JR, Milos PM, Agarwal S, Rao A. “Genome-wide mapping of 5-hydroxymethylcytosine inembryonic stem cells.” Nature. 2011 May 19;473(7347):394-7. Epub 2011 May 8. PMID: 21552279

Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A. “Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells.” Cell Stem Cell. 2011 Feb 4;8(2):200-13. PMID: 21295276

Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A. “Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.” Nature. 2010 Dec 9;468(7325):839-43. PMID: 21057493

Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A. “Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by the MLL fusion partner, TET1.” Science (2009) 324 (5929): 930-5. PMID: 19372391

Tahiliani M, Mei P, Fang R, Leonor T, Rutenberg M, Shimizu F, Li J, Rao A, Shi Y. “The Histone H3K4 Demethylase SMCX Links REST Target Genes to X-Linked Mental Retardation.” Nature (2007) 447: 601-5. PMID: 17468742

Click here to see all publications in PubMed