Timothy H. Bestor, PhD
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.
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
. 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