DS0405 -

Interplay between chromatin topological organization and alternative splicing regulation by RNA helicases DDX5 and DDX17 – CHROTOPAS

Submission summary

Cellular responses to environmental stimuli or transition from one cellular state to another are commonly defined by coordinated changes in gene expression, a complex process involving the production of mRNA molecules and their processing into mature transcripts. Of particular importance, alternative splicing events occur in 95% of human genes, shaping the transcriptome and massively expanding proteome repertoires according to cellular state. It is becoming more and more appreciated that gene expression regulatory processes are spatially coordinated and involve changes in chromatin topology. For example, chromatin loops bring distal enhancer elements into direct contact with their regulated gene promoters, and the enhancers’ ranges of activity appear in turn to be delimited by folding of the chromosome into distinct topologically associated domains (TADs). These “active chromatin hubs” of enhancer-gene complexes are in turn spatially organized into subnuclear structures which are concentrated in transcription and RNA processing factors. Transcription initiation and termination may also rely on gene looping. Recent studies have strengthened links between chromatin topology and transcription initiation, as well as between chromatin, transcription and splicing. However, the consequences of genome folding for splicing decisions have been barely studied, even though they are just as important for appropriate cellular responses and developmental fates.
We have recently shown that RNA helicases DDX5 and DDX17 orchestrate and finely tune gene expression programs during cell (trans)-differentiation, by acting at different levels including transcription and alternative splicing. Interestingly, these proteins interact with factors that control the chromatin topological organization. Because of that and because of the strong interplay between chromatin, transcription and splicing, we made the hypothesis that the regulation of alternative splicing by DDX5/DDX17 may result, at least in part, from their ability to promote specific changes in the spatial organization of their target genes, for example by establishing or disrupting chromatin loops around their targeted exons. On the basis of strong preliminary experiments that clearly support this hypothesis, our project will investigate the functional relationship between DDX5/DDX17 and DNA topology factors in terms of both gene expression and alternative splicing regulation. Using a variety of state-of-the-art large-scale approaches combined with molecular and cellular biology and molecular genetics approaches, we will study how this interplay impacts on the topological organization of DDX5/DD17-target genes and on alternative splicing of DDX5/DD17-target exons. These questions will be addressed in the context of neuronal differentiation and HTLV-1-infected T lymphocytes, two models in which we have shown DDX5 and DDX17 to play a major dynamic role. This innovative project will push forward the frontiers of our knowledge regarding the molecular mechanisms that control and coordinate DNA/chromatin topology, transcription and alternative splicing and should shed light on the notion that higher level of chromatin/DNA organization is important to shape the cellular transcriptome at both global gene expression and exon level resolution.

Project coordination

Didier AUBOEUF (Laboratoire de Biologie et Modelisation de la Cellule)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LBMC-CNRS Laboratoire de Biologie et Modelisation de la Cellule
IGBMC Institut de Génétique et de Biologie Moléculaire et Cellulaire

Help of the ANR 413,504 euros
Beginning and duration of the scientific project: - 42 Months

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