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H2020Individual fellowship2015–2017

GATTACA · Genetics of Alternative Transcript Abundance upon immune Cellular Activation

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2015-10-01 → 2017-09-30
EU contribution
€173,076
Participants
1
Scheme
MSCA-IF-EF-ST

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Results in brief

Genetics of Alternative Transcript Abundance upon immune Cellular Activation

Efficient immune response is fundamental to protect the cells from infection and keep individuals healthy. Yet, substantial variation in immune response is observed, both among individuals and populations. Genetics may contribute to these variations by controlling the total amount of RNA produced by a gene (transcripts), but also by altering the diversity of transcripts (or isoforms) that are produced by a single gene. This diversity is allowed by a mechanism known as alternative splicing, through which transcripts are cut and reassembled (i.e. spliced) during their maturation. To understand how genetic variants that alter splicing contribute to the variability of human immune responses, the GATTACA project aimed to: (1) identify master regulators of isoform diversity through the study of isoform regulatory networks in response to immune stimuli, (2) decipher the genetic bases of between-individual variations in isoforms abundance and identify DNA motifs that are essential to the regulation of isoform usage in an immune context, and (3) detect the mode and intensity of natural selection acting on splicing regulatory elements and splicing factors. All of these objectives have been successfully accomplished along the duration of the project. The most significant impact of the GATTACA project has been fundamental in nature by allowing us to better characterize the genetic bases of variability in the immune response to pathogens. However, these results will also be crucial to understand the mechanisms that contribute to immune disorders. Indeed, the GATTACA project has allowed to identify novel regulatory variants acting in the specific context of infection, some of which are associated to organismal traits, including response to vaccines, treatments and susceptibility to immune disorders, opening new avenues for the treatment of infectious, auto-immune and inflammatory disorders.

Data: CORDIS, © European Union

Project objective

The human body is constantly exposed to infectious agents. Efficient immune response is therefore fundamental to protect the cells from infection and keep individuals healthy. Still, extreme variations are observed in the efficiency of immune response among individuals and populations. Recently, the dissection of the genetic bases of the host immune response to infection has fostered a large interest in the scientific community. As a result, there is now a growing understanding of the influence of genetic variation on the transcriptional reprogramming of immune cells during infection. However, it is now widely accepted that the underlying ‘one gene–one protein’ paradigm is overly simplistic and cannot account for the full complexity of the transcriptome. Here, we propose to study how genetic variants affect transcript diversity to modulate the response to pathogens at the individual and population levels. To do so, we will seek to identify genetic variants that have conferred a selective advantage to human populations through modulation of isoforms usage in response to infection. This work will rely on an innovative strategy that combines coexpression-based studies of the isoform regulatory networks with analysis of the genetic determinants of splicing in response to infection. In doing so, this study should improve our understanding of isoform regulation and identify novel regulatory elements and splicing factor-target relationships in the specific context of infection.

Original text from CORDIS.

Participants

  • INSTITUT PASTEUR · ParisCoordinatorFrance

Links

Data: CORDIS, © European Union