Valerie Reinke, PhD

The genome carries all the information necessary for the development and function of an organism. This information is embedded at multiple levels - in the regulatory information of individual genes, in the partitioning of that sequence into chromatin domains, and in the spatial segregation of these domains into functionally distinct regions of the nucleus. This linear and spatial organization is essential for effective and precise deployment of genetic information, yet the underlying mechanisms that govern the three-dimensional architecture of the genome are just now being addressed, and fundamental questions remain unanswered: How does genome organization influence epigenetic information, and vice versa? How extensively does genome organization contribute to coordinated expression of functionally related genes? How does genome organization stabilize and instruct tissue-specific gene expression across generations?

We address these questions in vivo with unprecedented cell specificity and comprehensiveness, utilizing innovative methods to investigate how genome structure and organization influences gene expression specifically in the C. elegans germ line. Specific projects are focused on:

Temporally regulated expression of piRNA clusters. The C. elegans genome contains a remarkable genomic domain subject to tissue-specific expression. In C. elegans, thousands of individually transcribed loci encoding the piRNA class of small noncoding RNAs are clustered into two sharply demarcated regions on a single chromosome. piRNAs are germline- or stem cell-specific small RNAs that promote pluripotency and fertility in most organisms, including humans. piRNA clustering is evolutionarily conserved, indicating that physical proximity is a key feature for coordinated expression. We are working to dissect the mechanisms by which a long-range chromatin environment is established and deployed in germ cells to coordinate trans-generational expression of these densely clustered piRNA genes. We use cutting-edge genomic, molecular, and imaging methods to assay effects on piRNA gene expression and chromatin accessibility, and define how the memory of piRNA domain regulation is passed between parent and offspring. This work is broadly relevant to human health, as dysregulation of piRNAs occurs in somatic stem cells, cancer, and neurodegenerative diseases, as well as underlying male infertility.

Germline mechanisms that control trans-generational epigenetic information. A major goal of the lab is to determine how the action of three highly conserved chromatin-based mechanisms - nucleosome remodeling, histone modification dynamics, and histone variants - coordinately establish a germline gene expression program that anticipates and initiates the events of early embryogenesis. We have found that the germline-to-embryo transition requires the germline activity of two nucleosome remodelers, PBAF and ISWI, as well as the dynamic re-patterning of the histone modification trimethylated histone H3 lysine 4 (H3K4me3). We use cutting-edge genetic and genomic methods to induce assay the effects of disrupting these regulators on gene expression and chromatin accessibility in bulk and at single cell resolution. Thus, we seek to unravel the causal relationships between chromatin organization and the dynamics of germline gene regulation, and determine how the maternal germ line instructs the robust and reproducible events of early embryonic development.
The epigenetic regulators and dynamic chromatin behaviors we focus on are highly conserved and exert a strong influence on gene expression in humans, and thus will be highly translatable to fundamental causes of human disease.