Magee-Womens Research Institute & Foundation

Chromatin and Recombination

Chromosomes display a different propensity to missegregate during meiosis, suggesting that chromosome-specific features influence the pattern of nondisjunction. In humans and many other organisms, the sex chromosomes are distinguished from the autosomes by repetitive elements, sex-specific gene expression, histone modifications and degree of heterochromatinization. In C. elegans these differences have a profound effect on behavior of the X chromosome in the germ line, where the X chromosome is predominantly transcriptionally quiescent and heterochromatic. Studies in Drosophilaand mice have shown that heterochromatin presents a barrier to meiotic double-strand break (DSB) formation.

We have identified two genes, xnd-1 and him-5, required specifically for DSB formation on the X chromosome in C. elegans. Recent work in our lab has revealed that xnd-1 regulates specific histone modifications that differentially mark the sex chromosomes. The mouse knockout of the gene required for this modification shows reduced fertility, suggesting that further characterization of this pathway in the nematode will provide insight into mammalian fertility. The xnd-1 therefore provides a molecular handle into the study of how chromatin is regulated during meiosis and how it in turn shapes the genome.

Meiotic Crossover Checkpoints

The formation of crossovers during meiosis ensures their proper segregation at the first meiotic division. Therefore multiple checkpoints are active in the germline to guarantee the correct execution of these early meiotic events. Using xnd-1 and him-5 as tools to investigate the effects of having reduced crossover numbers, we have identified a surveillance system that monitors crossover formation chromosome-by-chromosome. Current projects are aimed at understanding the features that activate this checkpoint and signaling cascade that ensues.

Double-Strand Break Repair and Fertility

Double-strand breaks (DSBs) are the most toxic lesions encountered by our genome, yet during meiosis, they are purposefully made to promote crossovers between homologous chromosomes. Therefore the lab is interested in understanding how DSBs are made and coupled to downstream homologous recombination repair. Our analyses of him-5, cep-1, and rec-1 indicate that the break machinery “stacks the decks” to ensure HR repair by coupling DSB induction with downstream repair processes. Identifying and understanding the break machinery and the complexes and subcomplexes they comprise and how they are modified post-transcriptionally during meiosis are active areas of investigation within the lab.

Germ cell fate specification

In addition to its role in meiosis, xnd-1 plays a key role in early events of germ line fate development. Redundantly with the conserved germ line determinant, nanos, xnd-1 promote germ cell differentiation. Without xnd-1 and the nanos paralogs nos-1 and nos-2, animals develop without germ cells. XND-1 protein is the earliest known zygotic gene expressed in the primordial germ cells where is localizes to chromatin. Loss of xnd-1 function in the primordial germ cell is accompanied by expression of somatic markers and alteration in germline chromatin structure. We are using biochemical and genetic approaches to identify XND-1 binding partners to better understand its role in germ cell differentiation.

• Amrit FR, Steenkiste EM, Ratnappan R, Chen SW, McClendon TB, Kostka D, Yanowitz J, Olsen CP, Ghazi A. DAF-16 and TCER-1 Facilitate Adaptation to Germline Loss by Restoring Lipid Homeostasis and Repressing Reproductive Physiology in C. elegans. PLoS Genet. 2016;12(2):e1005788.
• Hillers KJ, Jantsch V, Martinez-Perez E, Yanowitz JL. Meiosis. WormBook. 2015:1-54.
• Mainpal R, Nance J, Yanowitz JL. A germ cell determinant reveals parallel pathways for germ line development in Caenorhabditis elegans. Development. 2015;142(20):3571-82.
• Chung G, Rose AM, Petalcorin MI, Martin JS, Kessler Z, Sanchez-Pulido L, Ponting CP, Yanowitz JL, Boulton SJ. REC-1 and HIM-5 distribute meiotic crossovers and function redundantly in meiotic double-strand break formation in Caenorhabditis elegans. Genes Dev. 2015;29(18):1969-79.
• Ghazi A, Yanowitz J, Silverman GA. Expanding the C. elegans toolbox into a toolshed. Methods. 2014;68(3):379-80.
• Zevian SC, Yanowitz JL. Methodological considerations for heat shock of the nematode Caenorhabditis elegans. Methods. 2014;68(3):450-7.
• Meneely PM, McGovern OL, Heinis FI, Yanowitz JL. Crossover distribution and frequency are regulated by him-5 in Caenorhabditis elegans. Genetics. 2012;190(4):1251-66.
• Graham PL, Yanowitz JL, Penn JK, Deshpande G, Schedl P. The translation initiation factor eIF4E regulates the sex-specific expression of the master switch gene Sxl in Drosophila melanogaster. PLoS Genet. 2011;7(7):e1002185.
• Vogel BE, Wagner C, Paterson JM, Xu X, Yanowitz JL. An extracellular matrix protein prevents cytokinesis failure and aneuploidy in the C. elegans germline. Cell Cycle. 2011;10(12):1916-20.
• Yanowitz J. Meiosis: making a break for it. Curr Opin Cell Biol. 2010;22(6):744-51.
• Wagner CR, Kuervers L, Baillie DL, Yanowitz JL. xnd-1 regulates the global recombination landscape in Caenorhabditis elegans. Nature. 2010;467(7317):839-43.
• Lim JG, Stine RR, Yanowitz JL. Domain-specific regulation of recombination in Caenorhabditis elegans in response to temperature, age and sex. Genetics. 2008;180(2):715-26.
• Yanowitz JL. Genome integrity is regulated by the Caenorhabditis elegans Rad51D homolog rfs-1. Genetics. 2008;179(1):249-62.
• Ward JD, Barber LJ, Petalcorin MI, Yanowitz J, Boulton SJ. Replication blocking lesions present a unique substrate for homologous recombination. EMBO J. 2007;26(14):3384-96.
• Yanowitz J, Fire A. Cyclin D involvement demarcates a late transition in C. elegans embryogenesis. Dev Biol. 2005;279(1):244-51.
• Yanowitz JL, Shakir MA, Hedgecock E, Hutter H, Fire AZ, Lundquist EA. UNC-39, the C. elegans homolog of the human myotonic dystrophy-associated homeodomain protein Six5, regulates cell motility and differentiation. Dev Biol. 2004;272(2):389-402.

For additional publications, visit Pubmed.

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