Unravelling the functional role of the “epigenetic reader” MRG-1 in the spatial organization of the C. elegans genome

点击翻译按钮获取中文摘要

Largely based on its transcriptional status, chromatin falls into two main classes: active euchromatin and transcriptionally repressed and compacted heterochromatin. Across species, the spatial distribution of euchromatin and heterochromatin is not random and enables a functional compartmentalization of the genome. In particular, silent heterochromatin is actively sequestered at the nuclear periphery, while active euchromatin is centrally located. Despite such a striking evolutionary conservation, to which degree the spatial sequestration of heterochromatin contributes to genome function is not fully understood. To formally address this, the factors and mechanisms that generate nuclear sub-compartments need to be identified and the consequences of their perturbation for gene expression must be elucidated.During my recent postdoctoral work, I identified MRG-1, the first component of the active chromatin compartment shown to be a critical for shaping heterochromatin spatial distribution in the intestine of C. elegans. Nonetheless, fundamental open questions remain as to how this regulation takes place. In particular, MRG-1 bears a chromo barrel domain that can “read” methylated histones. Yet, the chromatin signals that determine MRG-1 recruitment and function are not known. Furthermore, chromatin readers do not act alone and typically serve as recruiters of complexes to target sites. However, the MRG-1-containing complex responsible for heterochromatin organization is completely unknown.In this proposal, we aim to identify i) the histone marks, and corresponding chromatin modifiers, that participate in MRG-1 recruitment and contribute to its role in heterochromatin architecture and ii) the complex/protein interactors through which MRG-1 functions in heterochromatin organization, in the C. elegans intestine.To achieve our goals, my team will employ a combination of microscopy, genetic and biochemical approaches. Moreover, state-of-the-art molecular biology assays such as Emerin-DamID and RNAseq will provide us with integrated landscapes of chromatin compartmentalization and gene expression in the intestine of relevant mutants. With this work, we will identify novel players that shape the 3D organization of the genome within a differentiated tissue of a whole organism. Additionally, we will be able to determine their relevance for gene expression, at the tissue-specific level.Because MRG-1 and most chromatin factors are highly conserved between worms and mammals, this work is likely to have a broad impact in the field of epigenetics and nuclear architecture.