Biology subjects

Descostes, N.

Publications and source records attributed to Descostes, N..

9 recordsLinked to original sources

bioRxiv2022

Insulin signaling and extended longevity in ants

In most organisms, the cost of reproduction is a shorter lifespan. However, the reproductive caste in eusocial insect species (queen) exhibits an extraordinarily longer lifespan than non-reproductive castes (workers) despite having a similar genome, thus contradicting the aging dogma. In the absence of the queen, Harpegnathos saltator ants can undergo a caste switch from workers to reproductive pseudo-queens (gamergates). Gamergates exhibit a dramatically prolonged lifespan. When placed in the presence of a reproductive, they revert to worker status and their lifespan is then shortened accordingly. To understand this unique relationship between reproduction and longevity, we analyzed tissue-specific gene expression between castes. Insulin is upregulated in the gamergate brain that leads to oogenesis, but surprisingly correlates with extended longevity. This correlates with increased lipid synthesis and elevated production of vitellogenin in the fat body, which are both transported to the egg. We show that the production of vitellogenin in the fat body is due to the systemic activation of the MAPK branch of the insulin/IGF signaling (IIS)-pathway. In contrast, reduced expression of insulin receptors in the fat body of gamergates and the production in their developing ovary of an anti-insulin (Imp-L2) lead to the downregulation of the AKT/FOXO branch of the IIS-signaling pathway in the fat body, and to the dramatically extended longevity. This reveals a dual-pathway mechanism that reconciles increased longevity in the context of active reproduction in eusocial insects. One Sentence SummaryInsulin-dependent reproduction in ants correlates with extended longevity through insulin inhibition by anti-insulin Imp-L2.

physiology↗

bioRxiv2021

Identifying a novel role for the master regulator Tal1 in the Endothelial to Hematopoietic Transition

Recent progress in the generation of bona-fide Hematopoietic Stem and Progenitor Cells (HSPCs) in vitro and ex vivo has been built on the knowledge of developmental hematopoiesis, underscoring the importance of understanding in detail this developmental process. Here, we sought to elucidate the function of the hematopoietic regulators Tal1, Lmo2 and Lyl1 in the Endothelial to Hematopoietic Transition (EHT), the process through which HSPCs are generated from endothelial precursors during embryogenesis. We used a mouse embryonic-stem cell (mESC)-based differentiation system to model hematopoietic development, and combined gain-of-function experiments in sorted vascular smooth muscle cells (VSM) with multi-omics to obtain mechanistic insights into the mode of action of Tal1, Lmo2 and Lyl1. We found that these factors promote the silencing of the VSM transcriptional program and the activation of the hematopoietic one. Through this approach and the use of a Tet-on system to control the expression of Tal1 during hematopoietic specification from mESCs, we discovered that its expression in endothelial cells is crucial for the EHT to occur.

developmental biology↗

bioRxiv2021

The H3K36me2 writer-reader dependency in H3K27M-DIPG

The lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, the placement of methylation at lysine 27 of histone H3 (H3K27me2/3), promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation in vitro and tumorigenesis in vivo, and disrupts tumor-promoting gene expression programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers that mediate the pro-tumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Together, our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG and suggest a possibility to target this pathway for therapeutic interventions.

cancer biology↗

bioRxiv2019

Single-cell atlas of major haematopoietic tissues sheds light on blood cell formation from embryonic endothelium

The Yolk Sac (YS) and Aorta-Gonad-Mesonephros (AGM) are two major haematopoietic regions during embryonic development. Interestingly, AGM is the only one generating haematopoietic stem cells (HSCs). To identify the difference between AGM and YS, we compared them using single-cell RNA sequencing between 9.5 and 11.5 days of mouse embryonic development and identified cell populations using CONCLUS, a new computational tool. The AGM was the only one containing neurons and a specific mesenchymal population, while the YS major component was an epithelial population expressing liver marker genes. In addition, the YS contained a major endothelial population expressing Stab2, a hyaluronan receptor, also highly expressed by liver endothelium. We demonstrated that the YS haematopoietic potential was restricted to Stab2-negative cells and that ectopic expression of Stab2 could reduce blood cell formation from endothelium. Our results indicate that the AGM is a tissue more favourable to HSCs development than the YS because of its microenvironment and the nature of its endothelial cells.

developmental biology↗

bioRxiv2018

LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription

FACT (facilitates chromatin transcription) is a protein complex that allows RNAPII to overcome the nucleosome-induced barrier to transcription. While abundant in undifferentiated cells and many cancers, FACT is not abundant or is absent in most tissues. Therefore, we screened for additional proteins that might replace FACT upon differentiation. Here we report the identification of two such proteins, LEDGF and HDGF2, each containing two HMGA-like AT-hooks and a PWWP methyl-lysine reading domain known to bind to H3K36me2 and H3K36me3. LEDGF and HDGF2 localize with H3K36me2/3 at genomic regions containing active genes, usually adjacent to H3K27me3 domains. In myoblasts, where FACT expression is low, LEDGF and HDGF2 are enriched on most active genes. Upon differentiation to myotubes, LEDGF levels decrease across the genome while HDGF2 levels are maintained. Moreover, HDGF2 is recruited to the majority of myotube up-regulated genes and is required for their proper expression. HDGF2 knockout myoblasts exhibit an accumulation of paused RNAPII proximal to the first nucleosome within the transcribed region of many HDGF2 target genes, indicating a defect in early elongation. We propose that LEDGF and HDGF2 substitute for FACT in differentiated tissues and that their distribution on the genome helps maintain transcriptional programs unique to particular cell types.\n\nOne Sentence SummaryChromatin bound LEDGF and HDGF2 proteins allow RNAPII to overcome the nucleosome-induced block to transcription.

molecular biology↗

bioRxiv2018

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

A methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.

molecular biology↗

bioRxiv2018

Precise re-deposition of nucleosomes on repressive chromatin domains sustain epigenetic inheritance during DNA replication

Chromatin domains and their associated structures must be faithfully inherited through cellular division to maintain cellular identity. Yet, accessing the localized strategies preserving chromatin domain inheritance, specifically the transfer of parental, pre-existing nucleosomes with their associated post-translational modifications (PTMs) during DNA replication is challenging in living cells. We devised an inducible, proximity-dependent labeling system to irreversibly mark replication-dependent H3.1 and H3.2 histone-containing nucleosomes at single desired loci in mouse embryonic stem cells such that their fate after DNA replication could be followed. Strikingly, repressed chromatin domains are preserved through the local re-deposition of parental nucleosomes. In contrast, nucleosomes decorating active chromatin domains do not exhibit such preservation. Notably, altering cell fate leads to an adjustment in the positional inheritance of parental nucleosomes that reflects the corresponding changes in chromatin structure. These findings point to important mechanisms that contribute to parental nucleosome segregation to preserve cellular identity.

biochemistry↗

bioRxiv2018

Capturing the onset of PRC2-mediated repressive domain formation

Polycomb repressive complex 2 (PRC2) maintains gene silencing by catalyzing methylation of histone H3 at lysine 27 (H3K27me2/3) within chromatin. By designing a system whereby PRC2-mediated repressive domains were collapsed and then reconstructed in an inducible fashion in vivo, a two-step mechanism of H3K27me2/3 domain formation became evident. First, PRC2 is stably recruited by the actions of JARID2 and MTF2 to a limited number of spatially interacting \"nucleation sites\", creating H3K27me3-forming polycomb foci within the nucleus. Second, PRC2 is allosterically activated via its binding to H3K27me3 and rapidly spreads H3K27me2/3 both in cis and in far-cis via long-range contacts. As PRC2 proceeds further from the nucleation sites, its stability on chromatin decreases such that domains of H3K27me3 remain proximal, and those of H3K27me2 distal, to the nucleation sites. This study demonstrates the principles of de novo establishment of PRC2-mediated repressive domains across the genome.

genomics↗

bioRxiv2018

ChIPSeqSpike: A R/Bioconductor package for ChIP-Seq data scaling according to spike-in control

MotivationChromatin Immuno-Precipitation followed by Sequencing (ChlP-Seq) is used to determine the binding sites of any protein of interest. ChIP-Seq data suffer from being more qualitative than quantitative. The recent use of Spike-in controls along with the standard protocol tackled this problem. However, no dedicated tool is available for a robust evaluation of this new ChIP-seq approach\n\nResultsWe developed ChIPSeqSpike, an R/Bioconductor package that enables ChIP-Seq spike-in normalization, assessment and analysis. Ready to use scaled bigwig files and scaling factors values are obtained as output. ChIPSeqSpike also provides tools for ChIP-Seq spike-in assessment and analysis through a versatile collection of graphical functions.\n\nAvailabilityThe package is implemented in R (as of version 3.4) and is available from Bioconductor at the URL: https://www.bioconductor.org/packages/3.7/bioc/html/ChIPSeqSpike.html, where installation and usage instructions can be found.\n\nContactnicolas.descostes@nyumc.org

bioinformatics↗