Papers by Delara Saberan-Djoneidi
Cell Death & Disease
Prenatal inflammatory insults accompany prematurity and provoke diffuse white matter injury (DWMI... more Prenatal inflammatory insults accompany prematurity and provoke diffuse white matter injury (DWMI), which is associated with increased risk of neurodevelopmental pathologies, including autism spectrum disorders. DWMI results from maturation arrest of oligodendrocyte precursor cells (OPCs), a process that is poorly understood. Here, by using a validated mouse model of OPC maturation blockade, we provide the genome-wide ID card of the effects of neuroinflammation on OPCs that reveals the architecture of global cell fate issues underlining their maturation blockade. First, we find that, in OPCs, neuroinflammation takes advantage of a primed epigenomic landscape and induces abnormal overexpression of genes of the immune/inflammatory pathways: these genes strikingly exhibit accessible chromatin conformation in uninflamed OPCs, which correlates with their developmental, stage-dependent expression, along their normal maturation trajectory, as well as their abnormal upregulation upon neuroi...
HAL (Le Centre pour la Communication Scientifique Directe), Apr 25, 2019
We warmly thank the patients and their families for their participation in this study. We thank S... more We warmly thank the patients and their families for their participation in this study. We thank Slimane AIT-SI-ALI for helpful discussions and comments on the manuscript, Anne PLESSIS (Jacques Monod Institute, Paris, France) for helpful discussions on setting the SNAP-TAG technology, Anne VANET (Jacques Monod Institute, Paris, France) for helpful discussions on the HSF2 structural modelling. We thank Lauriane FRITSCH and Slimane AIT-SI-ALI (UMR7216, for HeLa-S3 cells and growth conditions for TAP-TAG analyses). We thank the Imaging Platform IMAGOSEINE and especially Nicole BOGETTO for her help in sorting the GFP-positive HeLa-S3 cells. We are grateful to Heinrich LEONHARDT (Ludwig-Maximilians University, Munich, Germany) for F3H cellular and molecular tools and Pierre-Antoine DEFOSSEZ and Laure FERRY (UMR7216) for helpful guidance in F3H and GFP-Trap experiments, Isabelle LEMASSON (East Carolina University, USA) for the KIX-GST constructs, and Sophie POLO (UMR7216) for SNAP-TAG vectors. We are grateful to Vincent El Ghouzzi for the kind gift of human induced pluripotent stem cells (hIPSCs). We thank Isabelle COUPRY and Benoit ARVEILER (CHU de Bordeaux, France) for primary skin fibroblasts from healthy donors. We thank the Institut Médical Jérôme Lejeune for the gift of Lymphoblastoid cells (patients 4 and 5). We are grateful to Delphine BOHL, and Stéphane BLANCHARD from Pasteur Institute (Rétrovirus et Transfert Génétique, INSERM U622) for their help in producing the retroviruses for TAP-TAG experiments in Hela-S3 cells. We thank Laure FERRY (UMR7216) and the Epigenomics Platform, as well as Sandra PIQUET (UMR7216) and the Microscopy Platform (UMR7216) for access to instruments and technical advice, and Clara GIANFERMI (UMR7216) for microscopy pictures of organoids and nSBs. We thank Isabelle Le PARCO and the staff from the Buffon animal housing facility at the
Human Genetics, Jun 1, 1994
The human 8.5 H probe was isolated from a human cerebellum cDNA library with a probe correspondin... more The human 8.5 H probe was isolated from a human cerebellum cDNA library with a probe corresponding to the coding region of the murine 8.5 M cDNA. This cDNA isolated from a murine cDNA library constructed from newborn cerebral hemispheres was selected because of its strong expression in embryonic neurons. Consequently the corresponding human gene could be a candidate for hereditary neurodegenerative diseases. The human 8.5 H gene was assigned by somatic hybrid analysis to chromosome 5; this chromosome contains the gene(s) for spinal muscular atrophy (SMA), a group of heritable degenerative diseases that selectively affect the anterior horn motor neuron of the spinal cord. The localization by in situ hybridization of 8.5 H on 5q35 excluded the possibility that this gene is identical to SMA. The SMA gene(s) was (were) known, from linkage analysis, to be in a region (5q11.2-q13.3) very distant from 5q35.
Journal of Biological Chemistry, 1995
The reshaping of the DNA methylome landscape after prenatal alcohol exposure (PAE) has been well-... more The reshaping of the DNA methylome landscape after prenatal alcohol exposure (PAE) has been well-documented in the adult brain, therefore a long time after the end of the exposure. However, the question of the immediate deposition or loss of DNA methylation marks in the prenatal neocortex, just after the end of PAE has not yet been directly addressed, genome widely.Using a binge-drinking-like model of PAE and capture of the DNA methylome, we have identified differentially methylated regions (DMRs) that are established immediately, within two hours after the end of PAE. Remarkably, these DMRs are prominently and statistically associated with: (i) enhancers that are active in the brain, associated with GO terms of importance for neurogenesis, neurodevelopment, and neuronal differentiation; (ii) genes that, in physiological conditions show dynamic gain in chromatin accessibility and/or upregulation of their expression in the time-window of exposure; (iii) imprinted genes and members of...
Cell Stress and Chaperones, 2021
Cancer cells rely on heat shock proteins (HSPs) for growth and survival. Especially HSP90 has mul... more Cancer cells rely on heat shock proteins (HSPs) for growth and survival. Especially HSP90 has multiple client proteins and plays a critical role in malignant transformation, and therefore different types of HSP90 inhibitors are being developed. The bioactive natural compound gambogic acid (GB) is a prenylated xanthone with antitumor activity, and it has been proposed to function as an HSP90 inhibitor. However, there are contradicting reports whether GB induces a heat shock response (HSR), which is cytoprotective for cancer cells and therefore a potentially problematic feature for an anticancer drug. In this study, we show that GB and a structurally related compound, called gambogenic acid (GBA), induce a robust HSR, in a thiol-dependent manner. Using heat shock factor 1 (HSF1) or HSF2 knockout cells, we show that the GB or GBA-induced HSR is HSF1-dependent. Intriguingly, using closed form ATP-bound HSP90 mutants that can be co-precipitated with HSF1, a known facilitator of cancer, w...
Addiction Biology, 2020
Ethanol consumption impairs learning and memory through disturbances of NMDA‐type glutamate recep... more Ethanol consumption impairs learning and memory through disturbances of NMDA‐type glutamate receptor‐dependent synaptic plasticity (long‐term depression [LTD] and long‐term potentiation [LTP]) in the hippocampus. Recently, we demonstrated that two ethanol binge‐like episodes in young adult rats selectively blocked NMDA‐LTD in hippocampal slices, increased NMDA receptor sensitivity to a GluN2B subunit antagonist, and induced cognitive deficits. Here, using knockout adult mice, we show that a stress‐responsive transcription factor of the heat shock factor family, HSF2, which is involved in the perturbation of brain development induced by ethanol, participates in these processes. In the absence of ethanol, hsf2−/− mice show a selective loss of LTD in the hippocampus, which is associated with an increased sensitivity of NMDA‐field excitatory postsynaptic potentials (fEPSPs) to a GluN2B antagonist, compared with wild‐type (WT) mice. These results suggest that HSF2 is required for proper ...
Cell Reports, 2020
Highlights d HSF2 is required to maintain cell-cell adhesion d HSF2 deficiency leads to downregul... more Highlights d HSF2 is required to maintain cell-cell adhesion d HSF2 deficiency leads to downregulation of cadherin superfamily genes d Impaired cell-cell adhesion sensitizes cells to prolonged proteotoxic stress d Cadherin-mediated cell-cell adhesion is a survival determinant upon proteotoxicity
Clinical Genetics, 2017
Patients suffering from psychiatric disorders have a life span burden, which represents an enormo... more Patients suffering from psychiatric disorders have a life span burden, which represents an enormous human, family, social, and economical cost. Several concepts have revolutionized our way of appraising neuropsychiatric disorders (NPDs). They result from a combination of genetic factors and environmental insults, and their etiology finds roots in the neurodevelopmental period. As epigenetic mechanisms tightly control brain development, exposure to adverse conditions disturbing the epigenetic landscape of the fetal brain increases the risk of developing NPDs, due to the persistence of abnormal epigenetic signatures, at distance from the initial stimulus. Here, we review these concepts and discuss recent results based on next‐generation sequencing (NGS) approaches that have shed light on the mechanisms that underlie the emergence of NPDs, highlighting the importance of epigenetic phenomena. Because epigenetic mechanisms are potentially reversible, unraveling the epigenetic contributio...
Journal of Biological Chemistry, 1998
We have isolated a full-length murine clone corresponding to the rat neuronal p1A75 partial cDNA ... more We have isolated a full-length murine clone corresponding to the rat neuronal p1A75 partial cDNA (Sutcliffe, J. G.
Nature Communications
Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or E... more Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models...
Cellular ability to maintain proper protein homeostasis (proteostasis) is essential for survival ... more Cellular ability to maintain proper protein homeostasis (proteostasis) is essential for survival upon protein-damaging conditions. Heat shock transcription factor 2 (HSF2) is one of the human HSFs activated in response to proteotoxic stress. HSF2 is dispensable for cell survival during acute heat stress, but its amount and DNA-binding activity increase under prolonged proteotoxic stress conditions, such as proteasome inhibition. Nevertheless, the specific role(s) of HSF2 and the global HSF2-dependent gene expression profile during sustained stress have remained elusive. We found that HSF2 is required for cell survival during prolonged proteotoxicity, as shown by treating wild-type and HSF2-deficient human osteosarcoma U2OS cells with the proteasome inhibitor Bortezomib. Strikingly, our RNA-seq analyses revealed that HSF2 disruption leads to marked downregulation of cadherin superfamily genes and subsequent functional impairment of cadherin-mediated cell-cell adhesion. We propose HSF...
Cells respond to protein-damaging insults by activating heat shock factors (HSFs), key transcript... more Cells respond to protein-damaging insults by activating heat shock factors (HSFs), key transcription factors of proteostasis. Abnormal HSF protein levels occur in cancer and neurodegenerative disorders, highlighting the importance of the tight control of HSF expression. HSF2 is a short-lived protein, but it is abundant in the prenatal brain cortex and required for brain development. Here, we reveal that HSF2 is acetylated and co-localized with the lysine-acetyl transferases CBP and EP300 in human brain organoids. Using unbiased, biochemical, cell-imaging, and in silico approaches, we show that CBP/EP300 acetylates HSF2 at specific lysine residues, which promotes HSF2 stabilization, whereas the lysine deacetylase HDAC1 catalyzes its proteasomal degradation. The CBP KIX domain and KIX-recognizing motifs in HSF2 are critical for its interaction with acetylating enzymes. The functional importance of acetylated HSF2 is evidenced in Rubinstein-Taybi syndrome (RSTS), characterized by mutat...
Developmental Biology, 2011
Nodal, a secreted factor known for its conserved functions in cell-fate specification and the est... more Nodal, a secreted factor known for its conserved functions in cell-fate specification and the establishment of embryonic axes, is also required in mammals to maintain the pluripotency of the epiblast, the tissue that gives rise to all fetal lineages. Although Nodal is expressed as early as E3.5 in the mouse embryo, its regulation and functions at pre-and peri-implantation stages are currently unknown. Sensitive reporter transgenes for two Nodal cis-regulatory regions, the PEE and the ASE, exhibit specific expression profiles before implantation. Mutant and inhibitor studies find them respectively regulated by Wnt/β-catenin signaling and Activin/Nodal signaling, and provide evidence for localized and heterogeneous activities of these pathways in the inner cell mass, the epiblast and the primitive endoderm. These studies also show that Nodal and its prime effector, FoxH1, are not essential to preimplantation Activin/Nodal signaling. Finally, a strong upregulation of the ASE reporter in implanting blastocysts correlates with a downregulation of the pluripotency factor Nanog in the maturing epiblast. This study uncovers conservation in the mouse blastocyst of Wnt/β-catenin and Activin/ Nodal-dependent activities known to govern Nodal expression and the establishment of polarity in the blastula of other deuterostomes. Our results indicate that these pathways act early on to initiate distinct cellspecification processes in the ICM derivatives. Our data also suggest that the activity of the Activin/Nodal pathway is dampened by interactions with the molecular machinery of pluripotency until just before implantation, possibly delaying cell-fate decisions in the mouse embryo.
Cell Stress and Chaperones, 2017
Abundant evidence has accumulated showing that fetal alcohol exposure broadly modifies DNA methyl... more Abundant evidence has accumulated showing that fetal alcohol exposure broadly modifies DNA methylation profiles in the brain. DNA methyltransferases (DNMTs), the enzymes responsible for DNA methylation, are likely implicated in this process. However, their regulation by ethanol exposure has been poorly addressed. Here, we show that alcohol exposure modulates DNMT protein levels through multiple mechanisms. Using a neural precursor cell line and primary mouse embryonic fibroblasts (MEFs), we found that ethanol exposure augments the levels of Dnmt3a, Dnmt3b, and Dnmt3l transcripts. We also unveil similar elevation of mRNA levels for other epigenetic actors upon ethanol exposure, among which the induction of lysine demethylase Kdm6a shows heat shock factor dependency. Furthermore, we show that ethanol exposure leads to specific increase in DNMT3A protein levels. This elevation not only relies on the upregulation of Dnmt3a mRNA but also depends on posttranscriptional mechanisms that are mediated by NADPH oxidase-dependent production of reactive oxygen species (ROS). Altogether, our work underlines complex regulation of epigenetic actors in response to alcohol exposure at both transcriptional and posttranscriptional levels. Notably, the upregulation of DNMT3A emerges as a prominent molecular event triggered by ethanol, driven by the generation of ROS.
Nous avons isole l'arnm 1190. 85 au decours d'un criblage differentiel destine a identifi... more Nous avons isole l'arnm 1190. 85 au decours d'un criblage differentiel destine a identifier des genes exprimes a un moment particulier de l'ontogenese du striatum. Cet arnm est long de 2100 bases et il est exprime specifiquement dans les neurones et les cellules neuroendocrines. Il code pour un polypeptide de 19 kda (p19). Sa sequence est tres similaire a celle de l'arnm p1a75 dont la caracterisation partielle realisee il y a une quinzaine d'annees avait montre qu'il codait pour une proteine specifiquement neuronale et potentiellement exprimee dans les dendrites. Nous avons isole adnc complet, long de 2090 bases, et qui code pour un polypeptide de 21 kda (p21). La comparaison des sequences des cdnas p19 et p21 murins et humains, suggere que les genes codants pour p19 et p21 sont issus de la duplication d'un gene ancetre, qui aurait eu lieu avant la divergence des mammiferes, et qui a probablement ete commune a toute une region chromosomique. Des etudes d&...
Premature birth is the commonest cause of death and disability in young children. Diffuse white m... more Premature birth is the commonest cause of death and disability in young children. Diffuse white matter injury (DWMI), provoked by inflammatory insults accompanying prematurity, is associated with increased risk of neurodevelopmental disorders - such as autism spectrum disorders - and is due to maturation arrest in oligodendrocyte precursors (OPCs). The lack of therapeutic solutions is a strong impetus to unveil the molecular mechanisms underlying neuroinflammation impact on OPC cell fate. We used a validated mouse model of DWMI, induced by systemic- and neuro-inflammation - as observed in preterm infants - and based on interleukin-1B administration from postnatal day P1 to P5. Using integrated genome-wide approaches we showed that neuroinflammation induced limited epigenomic disturbances in OPCs, but marked transcriptomic alterations of genes of the immune/inflammatory pathways. We found that these genes were expressed in control OPCs and physiologically downregulated between P3-P10...
EMBO Molecular Medicine, 2014
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Papers by Delara Saberan-Djoneidi