DS04 - Vie, santé et bien-être

Cardiogenic Genome Dynamics – CaGeD

Submission summary

Congenital heart disease is a major and increasingly prevalent health issue causing significant human and economic loss. Although progress has been made in surgical treatment and management of patients, the inability of adult heart to make a full functional recovery following insult leads to complications and heart failure. The Cardiogenic Genome Dynamics (CaGeD) project aims to provide a better understanding of the epigenetics underlying cardiac cell identity which may provide a basis for future therapeutic approaches designed to prevent pathologic remodelling and promote regeneration.

Intricate epigenetic mechanisms enable finely-tuned gene expression throughout an organism’s life. They include non-sequence modifications to DNA, such as DNA methylation, as well as higher order chromatin conformational changes. The later enable the vast numbers of non-coding regulatory elements, such as enhancers and promoters, to interact. Recent studies have highlighted the importance of cohesin and its loading partner Nipbl in mediating the formation of the resulting “DNA loops” that are a key aspect of transcriptional regulation.

Nipbl haploinsufficiency is by far the most common genetic defect in Cornelia de Lange Syndrome (CdLS) patients. It has been suggested that global gene mis-expression leads to the complex developmental phenotypes observed, including neuronal and cardiac defects.

At present, Nipbl-dependence of chromatin conformational changes required for cardiac progenitor specification has not been demonstrated. My working hypothesis is that several chromatin remodelling events, involving interactions with major transcription factors, are impaired in CdLS patients.

The first aim is to reveal Nipbl-cohesin dependent signaling in cardiac cells. I will investigate the signaling and chromatin accessibility in Nipbl conditional mutants, as well as interactions between Nipbl and the major cardiac transcription factor Nkx2.5. This will enable me to identify signaling pathways, genes and regulatory elements directly impacted by Nipbl deficiency.

The second aim is to reveal the major Nipbl-cohesin dependent chromatin conformational changes occurring in cardiac progenitors. For this I will overcome the current limitation with Nipbl ChIP-seq by generating an Nipbl-EGFP fusion cell line, -seq data from the two first aims will be analysed in order to identify key genes and regulatory elements targeted by Nipbl-cohesin in cardiac progenitors. 3C based approaches to reveal chromatin conformational changes mediated by Nipbl-cohesin involving these genomic regions.

The third aim is to attempt cardiogenesis rescue in CdLS model cell lines and mice. For this, murine and human cell CdLS models will be used and treated directly with Nipbl, or via signaling pathways identified in Aims 1 and 2.

In conclusion, the CaGeD project will provide novel and timely insight into the chromatin architecture associated with cardiac progenitor commitment, and the role of Nipbl in its establishment. This will assist the development of future therapeutic tools designed to target chromatin remodelling in order to promote regeneration or prevent pathologic signalling.

Project coordination

Thomas MOORE-MORRIS (Institut de Génomique Fonctionnelle)

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

U910 GENETIQUE MEDICALE ET Génomique Fonctionnelle
U1191 Institut de Génomique Fonctionnelle

Help of the ANR 219,017 euros
Beginning and duration of the scientific project: January 2018 - 36 Months

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