Guiding gene-specific methylation of histones in C. elegans

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2020

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Abstract

A cell’s function depends on its gene expression, which is controlled by two stores of information: the DNA sequence and the regulatory molecules that interact with DNA. While the information stored within DNA is well-studied, the function of regulatory molecules that influence gene expression is less understood. A key class of regulatory molecules is histone modifiers, which facilitate the methylation, acetylation, and other chemical modifications of histones. These modifications can affect the accessibility of DNA to enzymes that regulate gene expression. Histone modifications are conserved in multiple organisms, from fission yeast to mammals. However, there is contradictory evidence suggesting alternative roles for supposed inhibitory marks. Previous research has used mutations of histone-modifying enzymes to deduce the impact of the histone modifications on gene regulation. However, inferences from such experiments are complicated because the mutation can have an impact on a chromosomal scale, making it difficult to infer about single loci. Therefore, we are developing a dCas9-based platform to target histone modifiers, and their modifications, to a specific locus. Thus far we have found that dCas9 binding alone does not significantly disrupt gene expression within C. elegans, although we detected increased variation within somatic tissues of a ubiquitously expressed gene. Having completed this essential control, we will next introduce a histone modifier that adds H3K36me3 modifications to the same locus through a dCas9 fusion protein and determine its impacts on gene expression.

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