HIC1 : le noeud du problème en 17p13.3 ?

Le bras court du chromosome 17 (17p) est fréquemment altéré dans les cancers humains, notamment au niveau du gène p53. Cependant, dans certains cancers, des altérations en 17p concernent des régions distales de p53, en l’absence de toute mutation de ce gène. Des analyses de perte d’hétérozygotie et de méthylation des îlots CpG présents dans les promoteurs de gènes ont permis d’identifier en 17p13.3 plusieurs nouveaux gènes suppresseurs de tumeur proches les uns des autres, tels que HIC1 (hypermethylated in cancer 1) et OVCA1 (ovarian cancer gene 1). HIC1 est d’autant plus intéressant que l’extinction de son expression est, jusqu’à présent, préférentiellement due à l’hyperméthylation de son promoteur, et qu’il a été récemment décrit l’existence d’une boucle de régulation entre HIC1 et p53. Toutefois, si l’impact des modifications épigénétiques dans la tumorigenèse n’est plus à démontrer, les mécanismes orientant le choix d’une inactivation génique par des phénomènes épigénétiques ou génétiques restent à déterminer.Loss of heterozygosity (LOH) of the short arm of chromosome 17 (17p) is one of the most frequent genetic alterations in human cancers. Most often, allelic losses coincide with p53 mutations at 17p13.1. However, in many types of solid tumors including sporadic breast cancers, ovarian cancers, medulloblastomas and small cell lung carcinomas, frequent LOH or DNA methylation changes occur in a more telomeric region at 17p13.3, in absence of any p53 genetic alterations. These results suggest that one or more tumor suppressor genes located at 17p13.3 could be involved in tumorigenesis. In addition, the 17p13.3 region has also been implicated in the Miller-Dieker syndrome (MDS), a severe form of lissencephaly accompanied by developmental anomalies caused by heterozygous gene deletions. Analyses of deletion mapping and CpG island methylation patterns have resulted in the identification of two tumor suppressor genes at 17p13.3, HIC1 (hypermethylated in cancer 1) and OVCA1 (ovarian cancer gene 1). HIC1 is a tumor suppressor gene that encodes a transcriptional repressor with five Krüppel-like C2H2 zinc finger motifs and a N-terminal BTB/POZ domain. Clues to the tumor suppressor function of HIC1 have come from the study of heterozygous Hic1+/- mice, which develop spontaneous malignant tumors of different types. Generation of double heterozygous knockout mice Hic1+/-p53+/- provides strong evidence that epigenetically silenced genes such as HIC1 can significantly influence tumorigenesis driven by mutations of classic tumor suppressor genes. This functional cooperation between HIC1 and p53 is interesting and recently, its has been demonstrated that HIC1 was involved in a certain feedback regulation for p53 in tumor suppression through the histone deacetylase SIRT1. However, despite the fact that epigenetic oncogenesis is one of the most vibrant areas of biologic research, the determinants between genetic versus epigenetic routes of tumor suppressor gene inactivation remain elusive

Combined Laplacian-equivolumic model for studying cortical lamination with ultra high field MRI (7 T)

International audienceThe fine spatial resolution and novel contrasts offered by high-field magnetic resonance allow in vivo detection of histological layers in the cerebral cortex. This opens the way to in vivo analysis of cortical lamination, but the comparison of lamination profiles has proved challenging because the layers’ geometry is strongly influenced by cortical curvature. This paper introduces a model of the micro-structural organization of the cortex, which can compensate for the effect of cortical curvature. Layers are modelled by an equivolumic principle, while the vertical structure of the cortex is represented with a Laplacian model. In this framework, lamination profiles can be represented in a way that preserves the original voxel sampling of the acquisition. This model is validated on a magnetic resonance image of a post-mortem human brain acquired on a human 7 T scanner at 0.35 mm resolution

HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs).

The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation is dispensable for DNA repair since the non-SUMOylatable E316A mutant is as efficient as wt HIC1 in Comet assays. Upon induction of irreparable DSBs, the ATM-mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2. Moreover, irreparable DSBs strongly increase both the interaction of HIC1 with MTA1 and MTA3 and their binding to the SIRT1 promoter. To characterize the molecular mechanisms sustained by this increased repression potential, we established global expression profiles of BJ-hTERT fibroblasts transfected with HIC1-siRNA or control siRNA and treated or not with etoposide. We identified 475 genes potentially repressed by HIC1 with cell death and cell cycle as the main cellular functions identified by pathway analysis. Among them, CXCL12, EPHA4, TGFβR3 and TRIB2, also known as MTA1 target-genes, were validated by qRT-PCR analyses. Thus, our data demonstrate that HIC1 SUMOylation is important for the transcriptional response to non-repairable DSBs but dispensable for DNA repair

ELK1 Uses Different DNA Binding Modes to Regulate Functionally Distinct Classes of Target Genes

Eukaryotic transcription factors are grouped into families and, due to their similar DNA binding domains, often have the potential to bind to the same genomic regions. This can lead to redundancy at the level of DNA binding, and mechanisms are required to generate specific functional outcomes that enable distinct gene expression programmes to be controlled by a particular transcription factor. Here we used ChIP–seq to uncover two distinct binding modes for the ETS transcription factor ELK1. In one mode, other ETS transcription factors can bind regulatory regions in a redundant fashion; in the second, ELK1 binds in a unique fashion to another set of genomic targets. Each binding mode is associated with different binding site features and also distinct regulatory outcomes. Furthermore, the type of binding mode also determines the control of functionally distinct subclasses of genes and hence the phenotypic response elicited. This is demonstrated for the unique binding mode where a novel role for ELK1 in controlling cell migration is revealed. We have therefore uncovered an unexpected link between the type of binding mode employed by a transcription factor, the subsequent gene regulatory mechanisms used, and the functional categories of target genes controlled

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Caractérisation de l'interaction fonctionnelle entre le produit du gène suppresseur de tumeurs HIC1 et les protéines de la famille Polycomb

HIC1 (Hypermethylated in Cancer 1) est un gène suppresseur de tumeursinactivé dans de nombreux cancers par hyperméthylation de son promoteur ou pardélétion chromosomique. HIC1 joue également un rôle au cours du développement.En son absence, les souris meurent autour de la naissance et présentent desdéfauts de développement observés chez l Homme dans le Syndrôme de Miller-Dieker. La protéine HIC1 est un facteur de transcription possédant deux domainesde répression transcriptionnelle autonomes, son BTB/POZ N-terminal et sa régioncentrale, suivis de 5 doigts de zinc de type Krüppel C2H2 permettant sa fixation à uneséquence d ADN spécifique centrée sur un motif GGCA. Au cours de ma thèse, je me suis intéréssé aux mécanismes transcriptionnels mis en place par HIC1 afin de réprimer la transcription de ses gènes cibles. Dans cecadre, nous avons étudié son interaction fonctionnelle avec les protéines de lafamille Polycomb. HIC1 interagit avec hPCL3 et PHF1, deux protéines de la famillePolycomb-like, qui favorisent alors la formation d un complexe avec les membres duPRC2.Les Polycomb sont retrouvés sur une partie des gènes cibles cibles de HIC1et l inhibition de HIC1 dans des fibroblastes embryonnaires entraîne la délocalisationpartielle du PRC2 sur au moins un gène cible commun ATOH1. HIC1 est donc le premier facteur de transcription chez l Homme capable de recruter les Polycomb-like. En parallèle de ce travail, nous avons étudié les caractéristiques de l interaction entreles deux isoformes de hPCL3 et l histone méthyl-transférase EZH2. Dans une dernière partie, nous avons mis en évidence de nouveaux gènes cibles de HIC1 impliqués dans la migration et l invasion des cellules mammaires, deuxmécanismes dérégulés dans les carcinomes en absence de HIC1. ADRB2 code un récepteur membranaire dont l activation par l adrénaline en conditions de stress est fortement impliqué dans la croissance tumorale et le processus de métastase dansles cancers du sein. En tant que gène suppresseur de tumeurs, la réexpression de HIC1 inhibe celle d ADRB2 et impacte fortement la migration et l invasion de cellules mammaires malignes.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Identification de la séquence de fixation à l'ADN et de recherche de gènes cibles du produit du gène suppresseur de tumeurs HIC1

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Mécanismes différentiels de répression transcriptionnelle des gènes cibles de HIC1

HIC1 (Hypermethylated in Cancer 1) est un répresseur transcriptionnel codé par un gène suppresseur de tumeurs localisé en 17p13.3. Cette région est perdue ou inactivée par hyperméthylation dans de nombreux cancers humains ; et les souris hétérozygotes Hic+/- développent des tumeurs spontanées avec une incidence beaucoup plus élevée que les souris contrôle. Cette protéine est impliquée dans des boucles de régulation complexes impliquant p53, la désacétylase de classe III SIRT1 ainsi qu'une des protéines de contrôle du cycle cellulaire, E2F1. En réponse aux dommages à l'ADN, HIC1 réprime SIRT1, ce qui a pour conséquence l'augmentation du taux de p53 acétylée active. Ceci conduit à l'apoptose et à l'arrêt du cycle cellulaire. HIC1 étant lui-même activé par p53, cette boucle peut s'auto entretenir. Cette voie est également régulée par le métabolisme puisque la répression de SIRT1 par HIC1 est due, notamment, au corépresseur CtBP, lui-même régulé par la balance NADH/NAD+. D'autre part, et de manière intrinsèquement liée, cette même réponse aux dommages à l'ADN induit l'expression de HIC1 par E2F1. Ceci mène à une seconde boucle de régulation puisque HIC1 réprime E2F1, notamment lors de la phase de quiescence G0. Cette présente étude porte sur les différents mécanismes de répression transcriptionnelle mis en place par HIC1, sur ses gènes cibles déjà connus et nouvellement identifiés. Nous avons pu identifier un nouveau corépresseur de HIC1, MTA1, un membre du complexe NuRD, dont le recrutement est contrôlé par la compétition SUMOylation/Acétylation de la Lysine 314 de HIC1. De manière cohérente avec le rôle de HIC1 dans le contrôle de la croissance, le complexe HIC1-MTA1 est lié au promoteur de nouveaux gènes cibles, p57KIP2 et Cycline D1, dans des cellules quiescentes, ainsi qu'à un site nouvellement identifié au sein du promoteur de SIRT1. Tandis que le complexe NuRD apparaît réguler une majorité des gènes cibles de HIC1 connus à ce jour, ce n'est pas le cas pour CtBP, qui régulerait SIRT1 et un gène identifié récemment, CXCR7. De plus, HIC1 interagit avec le complexe SWI/SNF composé de l'ATPase BRG1 et de la sous-unité appartenant aux complexes répresseurs ARID1A, et ce pour réprimer E2F1, mais pas SIRT1, au sein de cellules primaires quiescentes. Ces résultats suggèrent la mise en place par HIC1 de mécanismes de répression transcriptionnelle complexes et finement régulés en fonction du type de gènes cibles et de l'état de la celluleLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF