Environment and Nuclear Organization

Multiple layers of regulation are required to establish and maintain appropriate gene expression patterns. These include chromatin modifications and higher order architecture of the genome.

From yeast to man, the spatial distribution of chromatin is not random and reflects its functional state: in most cells, transcriptionally silenced heterochromatin is actively sequestered at the nuclear and nucleolar periphery while active chromatin is centrally located. The establishment and definition of such spatial genomic architecture occurs during cell differentiation under developmental cues. But what happens to the large-scale 3D chromatin architecture under environmental stimuli? And is there a function for the spatial segregation of euchromatin and heterochromatin in the transcriptional response to unscheduled environmental stresses?

Our current work focuses on the role of nutrients and heat in modulating chromatin organization and tests its role as epigenetic effector of “stress memory,” a phenomenon that allows organisms to better respond to a second stress exposure later in life.

Enzymes that modify chromatin do so using metabolic intermediates as cofactors, therefore the nutritional state of an organism has the potential to directly impact the epigenome of its cells.

Which metabolites and dietary components influence chromatin function? What are the consequences of perturbing them for a developing organism?

In our group, we take advantage of the highly controllable/manipulatable diet and microbiota of C. elegans, to systematically screen for the metabolic requirements of heterochromatin silencing. Using a microscopy-based readout for heterochromatin state combined to genetic screens and microbiota strains we aim to i) identify metabolic enzymes, metabolites, and microbiota components that influence heterochromatin regulation in a multicellular organism and ii) characterize the consequences of their perturbations at the levels of chromatin organization, transcriptional output, and organismal health.

Within the nucleus, euchromatin (active) and heterochromatin (repressed) are spatially separated, with heterochromatin sequestered at the nuclear periphery. In several species, the heterochromatic mark H3K9 methylation is overall the main determinant for anchoring at the nuclear periphery. Nonetheless, H3K9me-independent pathways do exist. Surprisingly, we identified the euchromatic reader MRG-1 as required for the accurate sequestration of heterochromatin in the intestine of C. elegans (Cabianca et al., Nature 2019). In absence of MRG-1, heterochromatin detaches from the nuclear periphery and fails to remain silent, leading to a global perturbation of genome organization and function.

How does the euchromatin reader MRG-1 regulate heterochromatin spatial distribution? MRG-1 is part of multiple protein complexes, which one is responsible to preserve an accurate 3D chromatin organization?

Utilizing a combination of tissue-specific proteomics and genetic tools we aim to unravel the mechanism through which MRG-1 regulates genome architecture and transcription in intestine. Since MRG-1 is highly conserved in multicellular organisms, our work can shed light on conserved mechanisms governing chromatin architecture, potentially uncovering epigenetic contributors to cell identity and tissue homeostasis.