Phone: 607 253 4301
Fax: 607 253 4495
Studies in our lab are focused on the regulation of meiotic recombination and germ cell development by members of the DNA mismatch repair (MMR) family, and by other DNA repair pathways that, collectively, monitor and regulate the placement and frequency of meiotic crossovers (or chiasmata) resulting from homologous recombination. Failure to control the timing and frequency of these recombination events results in mis-segregation, or non-disjunction, of chromosomes that results in embryos that are either not viable (resulting in miscarriage) or in offspring with genetic disorders such as trisomy 21, or Down syndrome. We hypothesize that the MMR pathway plays an essential role in directing appropriate recombination since members of this pathway are found at recombination sites and since mutations in these genes result in premature chromosome separation. The role of the MMR family in this processes also depends on their interaction with key nucleases and helicases, including MUS81-EME1, EXO1, BLM, and SLX4, all of which provide an integrated regulatory process to ensure that each chromosome receives at least one crossover and that the crossovers are spaced appropriately to allow segregation of homologous chromsosomes at the first meiotic division.
To explore the role of the MMR pathway in human meiosis, we have recently begun to examine human female meiosis at the molecular level. These studies are aimed at elucidating recombinogenic events in human oocytes since little is known of these processes in humans and since the majority of trisomic disorders are the result of meiotic errors during female meiosis. We are particularly interested in the fate of human oocytes after meiotic recombination events have been resolved and in the genetic/environmental influences on recombination proficiency in human oocytes.
Additional studies in the lab are aimed at understanding the role of the Fanconi Anemia (FA) pathway in germ cell development and meiosis. This work stems from our observation that mouse mutants for SLX4, a newly recognized member of the FA pathway, and designated as FANC-P, is essential for germline stem cell proliferation and meiotic progression. Our extended studies are now focused on understanding how the entire FA network facilitates germline stem cell integrity.
A third area of focus in our lab involves the role of small RNA pathways in meiotic events, including initiation of meiosis and silencing of unpaired chromatin regions. We recently demonstrated that the Argonaute protein, AGO4, is essential for normal meiotic entry and silencing of the sex chromatin, and that it does this, at least in part, through the recruitment of numerous small RNA species. Excitingly, AGO4 localizes within the nucleus of meiotic cells, where it associates with regions of autosomes and sex chromosomes that happen to be unpaired, suggesting a role in heterochromatin-driven silencing events.
For further details, visit the Cohen Lab website.
- Sun X., Wu X., Cohen P.E. Non-Human primates exhibit errors in meiosis I. Molecular Reproduction and Development. In press (2012)
- Sun X., Cohen P.E. Studying recombination in mouse oocytes. Methods in Molecular Biology. In Press (2012)
- Modzelewski A.J., Holmes R.J., Hilz S., Grimson A., Cohen P.E. AGO4 regulates entry into meiosis and influences silencing of sex chromosomes in the male mouse germline. Developmental Cell. 23: 251-264 (2012)
- Holloway J.K., Mohan S., Balmus G., Sun X., Modzelewski A., Borst P.L., Freire R. Weiss R.S., Cohen P.E. Mammalian BTBD12 (SLX4) protects against genomic instability during mammalian spermatogenesis. PLoS Genetics 7(6): e1002094 (2011)
- Holloway J.K., Roberson E.K., Corbett K., Kolas N.K., Cohen P.E. NEK1 facilitates cohesin removal during mammalian spermatogenesis. Genes 2(1): 260-279 (2011)
- Cohen P.E., Holloway J.K. Computational approaches to modeling gene networks in human meiosis. Biology of Reproduction 82: 469-472 (2010) PMID: 20032284
- Holloway J.K., Morelli M.A., Cohen P.E. The Mouse Ortholog of the Human Bloom's Syndrome Mutated (BLM) is Critical for Integrating Multiple Pathways of Recombination during Meiosis. Journal of Cell Biology 188: 779-789 (2010). PMID: 20308424
- Paduch D.A., Bolyakov A., Cohen P.E., Travis A.J. Reproduction in men with Klinefelter syndrome: the past, the present, and the future. Seminars in Reproductive Medicine. 27(2):137-48 (2009).
- Kan R., Sun X., Kolas N.K., Wei K., Edelmann W, and Cohen P.E. Disruption of meiotic metaphase I in female mice carrying mutations in various components of the mismatch repair pathway. Biology of Reproduction. 78:462-471 (2008). PMID: 18057311
- Avdievich E., Reiss C., Scherer S.S., Jin B., Cohen P.E., Edelmann W. and Kneitz B. Distinct effects of an MLH1 ATPase mutation on MMR functions, cancer and meiosis. Proceedings of the National Academy of Sciences U.S.A. 105(11):4247-52. (2008). PMID: 18337503
- Svetlanov A., Baudat F., Cohen P.E., and DeMassy B. Distinct functions of MLH3 at recombination hot spots in the mouse. Genetics 178: 1937-1945 (2008). PMID: 18430927
- Morelli M., Werling U., Edelmann W., Roberson M.S., Cohen P.E. Analysis of Meiotic Prophase I in Live Mouse Spermatocytes. Chromosome Research 16: 743-760 (2008). PMID: 18516692
- Holloway J.K., Booth J., Edelmann W., McGowan C.H., Cohen P.E. MUS81 generates a subset of MLH1-MLH3 independent crossovers in mammalian meiosis. PLoS Genetics 4(9):e1000186 (2008). PMID: 18787696
- Holmes, R.J. and Cohen, P.E. Small RNAs and the RNAi pathway in meiotic prophase I. Chromosome Research 15:653-665 (2007). PMID: 17674152