Biology subjects

Jean-Christophe Grenier

Publications and source records attributed to Jean-Christophe Grenier.

3 recordsLinked to original sources

bioRxiv2015

Widespread shortening of 3’ untranslated regions and increased exon inclusion characterize the human macrophage response to infection

The contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with two live bacteria. In response to both bacteria we identified thousands of genes that significantly change isoform usage in response to infection, and found global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3 UTRs. Using complementary data collected in non-human primates, we show that these features are evolutionarily conserved among primates. Finally, our results suggest that the pervasive usage of shorter 3 UTRs is a mechanism for particular genes to evade repression by immune-activated miRNAs. Collectively, our results show that dynamic changes in RNA processing play a key role in the regulation of innate immune responses.

Genomics↗

bioRxiv2015

Bacterial Infection Remodels the DNA Methylation Landscape of Human Dendritic Cells

DNA methylation is thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a pathogenic bacteria is associated with rapid changes in methylation at thousands of loci. Infection-induced changes in methylation occur primarily at distal enhancer elements, including those associated with the activation of key immune-transcription factors and genes involved in the crosstalk between DCs and adaptive immunity. Active demethylation is associated with extensive epigenetic remodeling and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that rapid changes in methylation play a previously unappreciated role in regulating the transcriptional response of DCs to infection.

Genomics↗

bioRxiv2014

Recombination impacts damaging and disease mutation accumulation in human populations

Many decades of theory have demonstrated that in non-recombining systems, slightly deleterious mutations accumulate non-reversibly1, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion2, however it is not clear the extent to which these processes operate along recombining chromosomes with highly variable rates of crossing over. Using high coverage sequencing data from over 1400 individuals in The 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the genomic distribution of putatively deleterious variants across the entire human genome. We find that exons in regions of low recombination are significantly enriched for deleterious and disease variants, a signature that varies in strength across worldwide human populations with different demographic histories. As low recombining regions are enriched for highly conserved genes with essential cellular functions, and show an excess of mutations with demonstrated effect on health, this phenomenon likely affects disease susceptibility in humans.

Evolutionary Biology↗