Timothy H. Bestor, PhD

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Overview

Academic Appointments

  • Professor of Genetics & Development

Gender

  • Male

Research

DNA modification and epigenetic gene control in mammals.

Some mammalian promoters are inactive even when in the presence of all the factors necessary for their expression; imprinted genes and genes on the inactive X chromosomes are not expressed, even though the identical allele on the homologous chromosome may be expressed at high levels. The states of activity of such genes are subject to somatic inheritance. Genes subject to heritable silencing are said to be under epigenetic regulation. Most epigenetic regulation in mammals depends on the establishment and maintenance of genomic methylation patterns. Transcription of mammalian genes is prevented by the methylation of cytosines within promoter elements, and methylation patterns are transmitted during cell division with very high fidelity. It was previously thought that reversible promoter methylation might be involved in gene regulation during development, but recent data indicate that the primary function of DNA methylation is the suppression of intragenomic parasites and of proviral DNA. DNA methylation also has crucial roles in genomic imprinting and X chromosome inactivation in females. Our laboratory purified, characterized, and cloned the first eukaryotic DNA methyltransferase, now known as DNMT1. We collaborated with the Jaenisch laboratory to disrupt the Dnmt1 gene and showed that DNA methylation is necessary for the suppression of transposons; Jaenisch and colleagues showed that DNA methylation is required for imprinted gene expression and for X chromosome inactivation. Our laboratory was the first to identify a human genetic disorder (ICF syndrome) that is caused by mutations in a DNA methyltransferase gene (the DNMT3B gene), the first to identify a mammalian tRNA (cytosine-5) methyltransferase, and the first to identify a gene required for the establishment of genomic imprints in oocytes and for the methylation and silencing of transposons in male germ cells. We continue to identify the cues that direct de novo DNA methylation to specific sequences in germ cells and to identify factors required for de novo methylation. We are also using ultrahigh throughput DNA sequencing to obtain whole-genome methylation profiles in order to identify regions of ectopic DNA methylation that may contribute to the development of breast cancer and psychiatric disorders.

Grants

COMPREHENSIVE SINGLE MOLECULE ENHANCED DETECTION OF MODIFIED CYTOSINES IN MAMMALIAN GENOMES (Federal Gov)

Apr 19 2017 - Sep 30 2019

COMPREHENSIVE SINGLE MOLECULE ENHANCED DETECTION OF MODIFIED CYTOSINES IN MAMMALIAN GENOMES (Federal Gov)

Apr 19 2017 - Mar 31 2019

METHYLATION SUICIDE IN CANCER (PQ10) (Federal Gov)

Jun 1 2012 - May 31 2016

METHYLATION SUICIDE IN CANCER (PQ10) (Federal Gov)

Jun 1 2012 - May 31 2016

SUBPROJECT FOR INSTITUTION # 08-8795 (Federal Gov)

Sep 15 2009 - Aug 31 2014

GENOMIC METHYLATION PATTERNS AND MAMMARY CARCINOMA (Federal Gov)

May 17 2010 - Mar 31 2014

EPIGENETIC PROFILING OF MAJOR DEPRESSION (Federal Gov)

Jan 15 2009 - Oct 14 2011

EPIGENETIC PROFILING OF MAJOR DEPRESSION (Federal Gov)

Jan 15 2009 - Oct 14 2011

DIETARY METHYL CONTENT, EPIGENETICS AND BREAST CANCER (Federal Gov)

Jun 26 2006 - Apr 30 2011

DIETARY METHYL CONTENT, EPIGENETICS AND BREAST CANCER (Federal Gov)

Aug 1 2009 - Jul 31 2010

Selected Publications

1. Song, J., Rechkoblit, O., Bestor, T.H., Patel, D.J.: (2011) Structure of DNMT-1 DNA complex reveals a role for autoinhibition in maintenance DNA methylation . Science 331: 1036-40

2. Ooi, S.K., Wolf, D., Hartung, O., Agarwal, S., Daley, G.Q., Goff, S.P., and Bestor, T.H.: (2010) Dynamic instability of genomic methylation patterns in pluripotent stem cells

. Epigenetics Chromatin 3: 17-22

3. Boulard, M., Edwards, J.R. and Bestor, T.H. : (2015) FBXL10 protects Polycomb-bound genes from hypermethylation

. Nature Genetics 47: 479-85

4. Bestor, T.H., Edwards, J.R. and Boulard, M.: (2015) Notes on the role of dynamic DNA methylation in
mammalian development
. Proc Natl Acad Sci USA 112: 6796-9

5. Ooi, S. K., Qiu, C., Bernsten, E., Li, K., Jia, D., Yang, Z., Erdgument-Bromage, H.,Tempst, P., Lin, S-P., Allis, C.D., Cheng, X., Bestor, T.H. : (2007) DNMT3L connects de novo DNA methylation tounmethylated lysine 4 of histone H3 . Nature 448: 714-717

6. O'Donnell, A.H., Edwards, J.R., Rollins, R.A., Vander Kraats, N.D.,
Su, T., Hibshoosh, H.H., Bestor, T.H.: (2014) Methylation Abnormalities in Mammary Carcinoma: The Methylation Suicide Hypothesis. Journal of Cancer Therapy 5: 1311-1324