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Regulated gene expression underlies cell differentiation and development in higher eukaryotes. David Martin, MD, Senior Scientist at CHORI and Chair of the Center for Genetics, is interested in this process because of its fundamental role in creating phenotypic diversity in genotypically identical cells and organisms, and because it is disrupted in cancer cells. This interest has led him to investigate epigenetic inheritance and germline epimutation in mammals.

Transcription is controlled by the interaction of protein and RNA with DNA sequences in and around the coding regions of genes. Much evidence indicates that the transcriptional regulatory apparatus of higher eukaryotes serves primarily to determine if a gene will be actively transcribed, or maintained in a stable silent state (the state typical of a large proportion of the genome in differentiated cells). Investigation of this problem led to our studies of epigenetic variation and inheritance. Epigenetics is the study of heritable changes in gene function that are independent of DNA sequence. In mammals, phenotypic variation occurs in circumstances where genetic and environmental factors can be ruled out, and thus some variation may be epigenetic in origin. Dr. Martin and his collaborators have demonstrated that epigenetic marks can be maintained in the germ line and reversed in later generations, creating complex non-Mendelian inheritance patterns; furthermore they can be affected by environmental agents. This epigenetic system of phenotypic variation and inheritance is likely to have rules completely different from those of mendelian genetics.

Nearly half of the human genome is made up of repeated sequences, mostly retroelements, which are epigenetically silenced. These sequences may be spared in the resetting of epigenetic marks that occurs in the mammalian germline. Consideration of this possibility led us to suppose that genes in mammals could be subject to “epimutation”, stochastic and reversible germline silencing. In testing this hypothesis, we have identified individuals in whom a gene encoding the DNA mismatch repair gene MLH1 is epimutated, apparently as a germline event that can be maintained for at least one generation. These individuals have a clinical syndrome (HNPCC) indistinguishable that produced by germline genetic mutation of MLH1.

Dr. Martin’s current interests are the extent and mechanism of epigenetic inheritance in mammals, the development of models of stable epigenetic inheritance, and the disruption of epigenetic stability in senescence and cancer.



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