Chromatin is the site of numerous structural features that contribute to the regulation of the genome. Although numerous posttranslational modifications to the histone proteins that make up chromatin have been identified, it remains unclear whether and to what extent these modifications might regulate transposons and other repetitive sequences.
Although individual epigenetic modifications have been associated with actively transcribed regions in euchromatin, an emerging body of evidence suggests that Set1-mediated transcriptional control is often repressive.
My work explores this expanded role for the chromatin modifier complex Set1C/COMPASS as a regulatory module with roles throughout the genome, identifying novel locus-dependent repressive functions at repetitive genomic regions. Interestingly, Set1 has multiple repressive modes that are both dependent and independent of its canonical catalytic activity, methylation of histone lysines (H3K4me).
My work also explores how the movement of retrotransposons, theorized to be a principal driver of evolutionary change, is regulated by a combination of epigenetic and chromatin structural factors.
These studies have expanded the regulatory repertoire of an important histone modifier and highlight the multifaceted function of a highly conserved chromatin-modifying complex with diverse roles in genome control.
How the epigenome interacts with other nuclear components to control development, disease, and evolutionary change is in many ways an open question. In the future, I would like leverage synthetic biology and experimental evolution strategies to further define the epigenetic factors that influence how genomes adapt to selective pressures.
Jovan Cejovic, Jelena Radenkovic, Vladimir Mladenovic, Adam Stanojevic, Milica Miletic, Stevan Radanovic, Dragan Bajcic, Dragan Djordjevic, Filip Jelic, Milos Nesic, Jessica Lau, Patrick Grady, Nick Groves-Kirkby, Deniz Kural, Brandi Davis-Dusenbery. Using Semantic Web technologies to enable cancer genomics discovery at petabyte scale. Cancer Informatics. Submitted for publication, 2017.
Heather Murtona, Patrick Grady, Tsun Ho Chan, Hugh Cam, Simon Whitehall. Restriction of retrotransposon mobilization by transcriptional silencing and higher order chromatin organization. Genetics, August 1, 2016. vol. 203 no. 4 1669-1678
David Lorenz, Lauren Meyer, Patrick Grady, Michelle Meyer, Hugh Cam. Heterochromatin assembly and transcriptome repression by Set1 in coordination with a class II histone deacetylase. eLife 3, e04506 December 2014
Irina Mikheyeva, Patrick Grady, Fiona Tamburini, David Lorenz, Hugh Cam. Multifaceted genome control by Set1 dependent and independent of H3K4 methylation and the Set1C/COMPASS complex. PLOS Genetics, 2014 Oct 30;10(10):e1004740. doi: 10.1371/journal.pgen.1004740.