ENS - Départment de biologie

Mechanism of efficient double-strand break repair by a long non-coding RNA

Frédérique Godfroid — 2021-01-06T11:31:30Z

Roopa Thapar*, Jing L. Wang, Michal Hammel, Ruiqiong Ye, Ke Liang, Chengcao Sun, Ales Hnizda, Shikang Liang, Su S. Maw, Linda Lee, Heather Villarreal, Isaac Forrester, Shujuan Fang, Miaw-Sheue Tsai, Tom L. Blundell, Anthony J. Davis, Chunru Lin, Susan P. Lees-Miller*, Terence R. Strick*, John A. Tainer*.

Abstract

Mechanistic studies in DNA repair have focused on roles of multi-protein DNA complexes, so how long non-coding RNAs (lncRNAs) regulate DNA repair is less well understood. Yet, lncRNA LINP1 is over-expressed in multiple cancers and confers resistance to ionizing radiation and chemotherapeutic drugs. Here, we unveil structural and mechanistic insights into LINP1's ability to facilitate non-homologous end joining (NHEJ). We characterized LINP1 structure and flexibility and analyzed interactions with the NHEJ factor Ku70/Ku80 (Ku) and Ku complexes that direct NHEJ. LINP1 self-assembles into phase-separated condensates via RNA-RNA interactions that reorganize to form filamentous Ku-containing aggregates. Structured motifs in LINP1 bind Ku, promoting Ku multimerization and stabilization of the initial synaptic event for NHEJ. Significantly, LINP1 acts as an effective proxy for PAXX. Collective results reveal how lncRNA effectively replaces a DNA repair protein for efficient NHEJ with implications for development of resistance to cancer therapy.

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Nucleic Acids Res. 2020 Nov 4 ; 48(19) : 10953-10972. doi : 10.1093/nar/gkaa784

Cécile Charrier, lauréate du Prix Coups d'élan pour la Recherche Française 2020

Frédérique Godfroid — 2021-01-01T17:59:55Z

Améliorer les infrastructures et les conditions de travail des chercheurs en sciences de la vie
Le prix Coups d'élan pour la recherche française a été créé par la Fondation en 2000.
En vingt ans, 70 laboratoires français et plus de 500 chercheurs ont bénéficié de ce prix. Il est attribué chaque année à quatre équipes de recherche biomédicale publique, relevant de l'Inserm et de l'Institut des sciences biologiques du CNRS.

Quatre prix pour encourager les chercheurs en sciences de la vie
Au fil des années, la Fondation a constitué une série de quatre prix pour encourager les chercheurs en sciences de la vie dans les moments clés de leur carrière : le stage post-doctoral à l'étranger, le retour en France, la création d'une équipe, la reconnaissance de découvertes exceptionnelles. Ces quatre prix encouragent leurs lauréats à aller plus loin.

"La biologie des synapses nous éclaire sur l'évolution du cerveau d'Homo Sapiens"

Plus d'information sur le site de la Fondation Bettencourt

Video

An individual‐based model for the eco‐evolutionary emergence of bipartite interaction networks

Frédérique Godfroid — 2020-12-21T17:58:36Z

Abstract

How ecological interaction networks emerge on evolutionary time scales remains unclear. Here we build an individual‐based eco‐evolutionary model for the emergence of mutualistic, antagonistic and neutral bipartite interaction networks. Exploring networks evolved under these scenarios, we find three main results. First, antagonistic interactions tend to foster species and trait diversity, while mutualistic interactions reduce diversity. Second, antagonistic interactors evolve higher specialisation, which results in networks that are often more modular than neutral ones ; resource species in these networks often display phylogenetic conservatism in interaction partners. Third, mutualistic interactions lead to networks that are more nested than neutral ones, with low phylogenetic conservatism in interaction partners. These results tend to match overall empirical trends, demonstrating that structures of empirical networks that have most often been explained by ecological processes can result from an evolutionary emergence. Our model contributes to the ongoing effort of better integrating ecological interactions and macroevolution.

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Ecol Lett. 2020 Sep 4. doi : 10.1111/ele.13592.

Model-based inference of punctuated molecular evolution

Frédérique Godfroid — 2020-12-21T17:56:23Z

Abstract

In standard models of molecular evolution, DNA sequences evolve through asynchronous substitutions according to Poisson processes with a constant rate (called the molecular clock) or a rate that can vary (relaxed clock). However, DNA sequences can also undergo episodes of fast divergence that will appear as synchronous substitutions affecting several sites simultaneously at the macroevolutionary time scale. Here, we develop a model, that we call the Relaxed Clock with Spikes model (RCS), combining basal, clock-like molecular substitutions with episodes of fast divergence called spikes arising at speciation events. Given a multiple sequence alignment and its time-calibrated species phylogeny, our model is able to detect speciation events (including hidden ones) co-occurring with spike events and to estimate the probability and amplitude of these spikes on the phylogeny. We identify the conditions under which spikes can be distinguished from the natural variance of the clock-like component of molecular substitutions and from variations of the clock. We apply the method to genes underlying snake venom proteins and identify several spikes at gene-specific locations in the phylogeny. This work should pave the way for analyses relying on whole genomes to inform on modes of species diversification.

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Mol Biol Evol. 2020 Jun 10 ; msaa144. doi : 10.1093/molbev/msaa144.

David Holcman, lauréat de l'appel d'offre ERC "Advanced Grants" 2019

Frédérique Godfroid — 2020-12-18T14:01:36Z

Pour son projet, OrganellenanoComp | "Computational methods and modeling to decipher organelle nanophysiology"

Ces bourses ERC permettent aux scientifiques de mener des projets en rupture qui ouvrent des voies innovantes dans leur champ disciplinaire.

Plus d'info à propos de l'ERC Advanced Grants 2019 :
– ENS-PSL, Focus David Holcman
– Communiqué de presse du CNRS
– Communiqué de presse ERC du 31 Mars 2020
– Résultats de l'appel ERC Advanced 2019-Horizon 2020

Cis-acting variation is common across regulatory layers but is often buffered during embryonic development

Frédérique Godfroid — 2020-12-17T16:31:33Z

Swann Floc'hlay, Emily Wong, Bingqing Zhao, Rebecca R Viales, Morgane Thomas-Chollier, Denis Thieffry, David A Garfield, Eileen E. M. Furlong*

Abstract

Precise patterns of gene expression are driven by interactions between transcription factors, regulatory DNA sequence, and chromatin. How DNA mutations affecting any one of these regulatory 'layers' is buffered or propagated to gene expression remains unclear. To address this, we quantified allele-specific changes in chromatin accessibility, histone modifications, and gene expression in F1 embryos generated from eight Drosophila crosses at three embryonic stages, yielding a comprehensive dataset of 240 samples spanning multiple regulatory layers. Genetic variation (allelic imbalance) impacts gene expression more frequently than chromatin features, with metabolic and environmental response genes being most often affected. Allelic imbalance in cis-regulatory elements (enhancers) is common and highly heritable, yet its functional impact doesn't generally propagate to gene expression. When it does, genetic variation impacts RNA levels through H3K4me3 or independently through chromatin accessibility and H3K27ac. Changes in RNA are more predictive of variation in H3K4me3 than vice versa, suggesting a role for H3K4me3 downstream of transcription. The impact of a substantial proportion of genetic variation is consistent across embryonic stages, with 50% of allelic imbalanced features at one stage being also imbalanced at subsequent developmental stages. Crucially, buffering, as well as the magnitude and evolutionary impact of genetic variants, are influenced by regulatory complexity (i.e., number of enhancers regulating a gene), with transcription factors being most robust to cis-acting, but most influenced by trans-acting variation.

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Genome Res. 2020 Dec 11 ; gr.266338.120. doi:10.1101/gr.266338.120

Bidirectional control of fear memories by cerebellar neurons projecting to the ventrolateral periaqueductal grey

Frédérique Godfroid — 2020-12-09T14:29:53Z

Abstract

Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. Moreover, FN-vlPAG projections also modulate extinction learning. We also found a FN-parafascicular thalamus pathway, which may relay cerebellar influence to the amygdala and modulates anxiety behaviors. Overall, our results reveal multiple contributions of the cerebellum to the emotional system.

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Nat Commun. 2020 Oct 15 ;11(1):5207. doi:10.1038/s41467-020-18953-0

A broad mutational target explains a fast rate of phenotypic evolution

Frédérique Godfroid — 2020-12-07T20:21:44Z

Abstract

The rapid evolution of a trait in a clade of organisms can be explained by the sustained action of natural selection or by a high mutational variance, that is the propensity to change under spontaneous mutation. The causes for a high mutational variance are still elusive. In some cases, fast evolution depends on the high mutation rate of one or few loci with short tandem repeats. Here, we report on the fastest evolving cell fate among vulva precursor cells in Caenorhabditis nematodes, that of P3.p. We identify and validate causal mutations underlying P3.p's high mutational variance. We find that these positions do not present any characteristics of a high mutation rate, are scattered across the genome and the corresponding genes belong to distinct biological pathways. Our data indicate that a broad mutational target size is the cause of the high mutational variance and of the corresponding fast phenotypic evolutionary rate.
Keywords : C. elegans ; caenorhabditis ; evolutionary biology ; evolutionary rate ; genetics ; genomics ; mutational target ; mutational variance ; vulva.

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Elife. 2020 Aug 27 ;9:e54928. doi : 10.7554/eLife.54928.

Antoine Triller lauréat de l'appel d'offre ERC "Synergy Grants"

Frédérique Godfroid — 2020-11-09T20:53:49Z

ERC Synergy Grants are intended to enable minimum two to maximum four Principal Investigators and their teams to bring together complementary skills, knowledge, and resources in new ways, in order to jointly address ambitious research problems.

Titre du projet : “Microglia Control of Physiological Brain States”
Say the word “brain”, and most of us envisage a complex network of neurons sending electric signals all over the body. But this neurocentric view is too simplistic. This fantastic machine has other important parts - and microglia are its unsung heroes. They act as the local immune system, protecting our brains from infections and making sure nothing goes wrong. Scientists, however, have speculated that microglia may have additional functions.
A team of four researchers based in Germany, France and the US has just been awarded an ERC Synergy Grant to study the “Microglial Control of Physiological Brain States”. They propose that reciprocal signaling between neurons and microglia is critical for a healthy brain. The language of this intercellular communication is largely unknown. “It will be like deciphering the Rosetta Stone”.
Nils Brose, Thomas Oertner, Anne Schaefer and Antoine Triller will combine their unique skill sets - ranging from gene expression analysis to cutting-edge imaging technologies - to investigate the role of microglia and bring these little cells into the spotlight they deserve. In doing so, they will paint a more complete picture of how the brain works, shedding light on some of its complex mysteries and advancing the fight against neurological disorders.

More information about Synergy Grants 2020
More information about Synergy Grants Projects, examples

Camille Berthelot, lauréate de l'appel d'offre ERC "Starting Grants" 2019

Frédérique Godfroid — 2020-10-13T14:03:58Z

Pour son projet, EvoMens | "The evolution of menstruation in primates"

Ce contrat finance de jeunes chercheurs de toutes nationalités, pour leur permettre de mener des projets de recherche innovants et de très haut niveau.

More info on Starting Grants 2019 ERC