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Spatio-temporal Organization and Expression of the Genome

Periodic Reporting for period 3 - 4D-GenEx (Spatio-temporal Organization and Expression of the Genome)

Reporting period: 2021-04-01 to 2022-09-30

Our genome is an ensemble of long DNA molecules within the nucleus of our cells. It has more than 20 000 genes, i.e. portions of the DNA molecule that can be read – or rather expressed – to produce proteins with various functions. Every cell of our body expresses a certain subset of those genes, allowing to fulfill its role in the organism. We know that cancer can start and progress when a cell takes a wrong decision to abnormally express one or more genes (called oncogenes), leading to appearance of tumors (where cells proliferate uncontrollably, migrate and metastasize to other regions of the body). It is a major challenge for contemporary biology to understand how these decisions are made within cells.

Thanks to the recent technological progress, we know that 3D genome conformation plays the key role in gene expression. In particular, we know that certain genes are often found in proximity in 3D space inside the nucleus. Also, the spatial folding of the genome allows certain genomic regions called ‘enhancers’ to influence the decision whether to express a gene or not. There are many examples where it is directly the perturbation of 3D genome folding that activates oncogenes, especially in many carcinomas. Despite those observations, our understanding of the mechanisms at play, in healthy and pathological contexts, is still limited.

Using breast cancer cells, we study distinct sets of genes that are sensitive to the hormone estrogen. Using cutting-edge microscopy, we observe the 3D positions and activity (expressed or not) of each of these genes. We combine this approach technologies, such as CRISPR and others, to perturb different factors (mutations, inactivation of enhancers) as to understand the fundamental mechanisms governing the decisions to express genes or not.
We have shown that the way DNA molecules are folded locally (i.e. at a scale of about 1/100 of their total length) affects how several genes are regulated. More precisely, we have shown how this local folding is a way for the cells to co-regulate in a similar way several genes at a time. We are currently using CRISPR to artificially make a genetic mutation that mimics what is known to happen in certain cancers, as to understand the role this mechanism can have in disease progression.
At a different scale, we are also studying genes that are distributed throughout the genome (i.e. on different chromosomes). We chose genes that are all responding to the hormone estrogen with the goal to understand how they re-arrange globally in space in relation with their response to estrogen. Our goal here is to understand how the organization of 3D space in the nucleus of our cells participate in the decisions to express our genes.