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Defining the role of subnuclear concentration of heterochromatinassociated proteins in genome organization and silencing

Research Project
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01.01.2021
 - 01.01.2022

During eukaryotic development, the genome organizes itself non-randomly into regions of active euchromatin and inactive heterochromatin that differ in their nuclear positioning and preference for long-distance genomic interactions. Post-translational modifications of histones are associated with genome activation or repression in these distinct compartments. Specifically, methylation of histone H3 lysine 9 (H3K9me) marks regions of constitutive heterochromatin, and conserved H3K9 histone methyltransferases (HMTs) have been shown to be able to drive perinuclear anchoring of heterochromatin and to reinforce topologically associated domains (TADs) between repressed regions of the genome. However, it remains unclear whether these HMTs promote TAD formation through mechanisms over and above their enzymatic activity, which is important because amplification or mistargeting of H3K9 HMTs is associated with tumor progression in many cancers. We recently demonstrated in C. elegans that the H3K9 HMT SETDB1 homolog MET-2 associates with an unstructured cofactor LIN-65/ATF7IP to become enriched at dynamic subnuclear foci that behave similarly to phase-separated condensates. Competence to make foci via interaction with LIN-65 was critical for H3K9 methylation, transcriptional repression, and germline viability. Surprisingly, MET-2 can make foci and preserve germline viability independent of its catalytic activity, leading us to hypothesize MET-2 foci themselves contribute physically to heterochromatin stability. To better understand how MET-2 contributes to silencing, we propose to: 1) map the genomic loci with which MET-2 foci stably interact and measure the transcriptional consequences of that interaction; and 2) demonstrate how MET-2 foci influence chromosome shape, long-range contacts, and epigenetic signatures across developmental time. These findings will demonstrate the importance of nuclear membrane-less compartments in higher order chromatin structure in an intact, multicellular organism as well as suggest new avenues for targeting H3K9 HMTs in disease.

Members (2)

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Susan Elizabeth Mango

Principal Investigator
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Colin Delaney

Project Member