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Meiotic crossovers are essential for proper chromosome segregation during egg and sperm development, but our understanding of the factors that influence where crossovers occur on chromosomes is lacking. We have identified seven uncharacterized chromatin-associated proteins that influence crossover distribution using RNA interference. To validate these results and begin to investigate gene function, we need to create deletion alleles of these loci using CRISPR and perform cytological analysis of meiotic chromosome behaviors. Longterm, we want to use ChIP-Seq studies to identify the protein binding sites and how this correlates with crossover patterns.
We recently identified the GCNA protein as an ancestrally-conserved regulator of germ line genome integrity. GCNA belongs to the class of proteins with intrinsically disordered regions (IDRs), which are known to undergo phase transitions to mediate cellular processes. Using Mass Spectrometry in multiple species, we have identified putative conserved binding partners of GCNA that may regulate cell division. To begin to characterize their function, we need to create CRISPR mutant and tagged alleles in C. elegans. Evolutionarily, these proteins are intriguing because they appeared to evolve as gene pairs in nematodes, but not other species, providing an opportunity to do computational modeling of protein evolution related to gene function.
CHARGE syndrome is a neurodevelopmental disorder caused by mutations in the CHD7 locus. We have created a C. elegans model of CHD-7 impairment and have found that this protein regulates senescence. CHARGE syndrome has a range of developmental phenotypes and, likewise in the worm, this chromatin remodeling protein appears to control multiple aspects of developmental. We are interested in identifying CHD-7 gene targets throughout development using combinations of RNA-Seq and ChIP-Seq studies. Further studies of chd-7 mutants will focus on its role in regulating germ cell tumor formation in the worm model.
- Ph.D. in Molecular Biology-Princeton University 1999
- B.S. in Biology-MIT 1991
Bhargava V, Goldstein CD, Russell L, Xu L, Ahmed M, Li W, Casey A, Servage K, Kollipara R, Picciarelli Z, Kittler R, Yatsenko A, Carmell M, Orth K, Amatruda JF*, Yanowitz JL*, and Buszczak M*. 2020. GCNA protects genome integrity and fertility across species. Dev Cell. 52(1):38-52; DOI:https://doi.org/10.1016/j.devcel.2019.11.007 *co-corresponding authors.
Li W and Yanowitz JL. 2019. ATM and ATR Influence Meiotic Crossover Formation Through Antagonistic and Overlapping Functions in Caenorhabditis elegans. Genetics. Jun;212(2):431-443. doi: 10.1534/genetics.119.302193
Ahuja JS, Sandhu R, Mainpal R, Lawson C, Henley H, Hunt PA, Yanowitz JL, Börner GV. 2017. Control of meiotic pairing and recombination by chromosomally tethered 26S proteasome. Science. Jan 27;355(6323):408-411. doi: 10.1126/science.aaf4778. Epub 2017 Jan 5. PMID:28059715
Macaisne N, Kessler Z, Yanowitz JL. 2018. Meiotic Double-Strand Break Proteins Influence Repair Pathway Utilization. Genetics. Sep 21; pii: genetics.301402.2018. doi: 10.1534/genetics.118.301402.
Machovina TS, Mainpal R, Daryabeigi A, McGovern O, Paouneskou D, Labella S, Zetka M, Jantsch V, Yanowitz JL. 2016. A Surveillance System Ensures Crossover Formation in C. elegans. Curr Biol. Nov;26(21):2873-2884. doi: 10.1016/j.cub.2016.09.007. PMCID:PMC5104180
Each day, our genome is confronted with hundreds of insults that damage our DNA and must be repaired to ensure the proper functioning our cells and the faithful segregation of our genetic material to the next generation. The work in the Yanowitz lab uses the nematode, Caenorhabditis elegans, to molecularly and genetically characterize the processes that maintain genome integrity in developing germ cells. The current studies are divided into three mains area of research, 1) understanding the molecular events drive reproductive aging; 2) characterizing the molecular process that monitor meiotic crossover formation; 2) identifying and characterizing novel genome integrity factors.
Chromosome missegregation during the formation of egg and sperm are major causes of miscarriage and infertility. Further, greater than seventy percent of miscarriages arises from defects in meiotic crossover recombination. Our studies have identified proteins that control when, where and how many crossovers occur per chromosome. These studies provide insight into the etiology of human chromosome abnormalities by illuminating why some chromosomes are more susceptible to missegregation than others. These studies led us to identify a crossover surveillance system that ensures that each chromosome receives an exchange and delays development if they have not. Understanding how this system works may be exploited to identify oocytes that have properly executed all of the events of meiosis. Lastly, we have identified several key proteins that have dual roles in meiotic DNA repair and replicative repair, ensuring that meiotic exchanges and repair of double-strand breaks from genotoxic exposure are repaired with high fidelity. Thus, deeper understanding of these proteins may provide insights into both reproductive health, as well as cancer.
