New mechanisms for targeting epigenetic silencing

Transcriptional silencing is important to prevent expression of transposable elements that may deregulate the genome once activated. Broadly, transcriptional silencing involves local modifications of the composition of chromatin to a specialized silencing form called heterochromatin. However, the mechanisms that target the deposition of heterochromatin remain unclear. The chromatin remodeler Decreased DNA Methylation 1 (DDM1) was identified 25 years ago as a main controller of transposon silencing and more recently was shown to deposit heterochromatin. Most chromatin remodelers function as protein complexes but DDM1 has remained exceptional by the absence of interacting proteins that could form a complex and target DDM1 to transposable elements. The objective of this proposal is to identify proteins forming a DDM1 complex including trans-acting factors that could target DDM1 to transposable elements. Two main research axes are proposed: a genetic screen and proximity labelling. These will identify direct interactors of DDM1 and a combination of genetics, genomics and biochemistry will establish the role of DDM1 interactors in silencing transposable elements. DDM1 is the major pathway silencing transcriptionally TEs in plants. The identification of trans-acting DDM1 interactors would provide means to engineer new targeted transcriptional silencing strategies in crops. This form of silencing could be epigenetically inherited across generations in absence of the initial targeting event. DDM1 orthologs in mammals are involved in prevention of severe epigenetic disorders. The trans-acting interactors of DDM1 might show a strong degree of conservation in mammals and be of interest for targeting pharmacological agents.

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