Organismal development is controlled by gene regulatory events that are activated in a precise spatiotemporal manner. This is tightly linked to epigenetic modifications, which play a critical role in determining cell fate. A pathway of developmental timing (heterochronic) genes was first identified in the nematode C. elegans from studies of a stem cell-like population of cells, the hypodermal seam cells. Components of this pathway have been shown to be evolutionarily conserved in mammals where they play important roles in stem cell fate, affecting events such as cell division, proliferation, and differentiation. These genes are emerging as key players in the studies of development and cancer progression. We aim to identify epigenetic regulators that control cell-fate decision between proliferation and differentiation using this C. elegans pathway, with the broader goal of elucidating the mechanisms by which conserved epigenetic factors regulate pluripotency and oncogenesis in mammals. We are studying the chromatin remodeler SWI/SNF genes, shown to have mutations in 20% of human cancers, to understand the mechanism in which these genes control cell fate. To address this question, we first generated a tool to study the role of genes specifically in the C. elegans seam cells by creating transgenic animals that contain the Cas9 gene under a seam cell-specific promoter (Pceh-16). We generated CRISPR/Cas9 swsn-1 and swsn-6 mutants to observe their effect on seam cell development. We hope to create a complete set of seam cell-specific SWI/SNF mutant animals, which would help shed light on the epigenetic mechanisms underlying development and cancer.

Tissue-specific CRISPR/Cas9 mutants: A tool to study the role of epigenetics in stem cells

253rd National Meeting (2017)

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