Genome-Wide Characterization of Menin-Dependent H3K4me3 Reveals a Specific Role for Menin in the Regulation of Genes Implicated in MEN1-Like Tumors

Inactivating mutations in the MEN1 gene predisposing to the multiple endocrine neoplasia type 1 (MEN1) syndrome can also cause sporadic pancreatic endocrine tumors. MEN1 encodes menin, a subunit of MLL1/MLL2-containing histone methyltransferase complexes that trimethylate histone H3 at lysine 4 (H3K4me3). The importance of menin-dependent H3K4me3 in normal and transformed pancreatic endocrine cells is unclear. To study the role of menin-dependent H3K4me3, we performed in vitro differentiation of wild-type as well as menin-null mouse embryonic stem cells (mESCs) into pancreatic islet-like endocrine cells (PILECs). Gene expression analysis and genome-wide H3K4me3 ChIP-Seq profiling in wild-type and menin-null mESCs and PILECs revealed menin-dependent H3K4me3 at the imprinted Dlk1-Meg3 locus in mESCs, and all four Hox loci in differentiated PILECs. Specific and significant loss of H3K4me3 and gene expression was observed for genes within the imprinted Dlk1-Meg3 locus in menin-null mESCs and the Hox loci in menin-null PILECs. Given that the reduced expression of genes within the DLK1-MEG3 locus and the HOX loci is associated with MEN1-like sporadic tumors, our data suggests a possible role for menin-dependent H3K4me3 at these genes in the initiation and progression of sporadic pancreatic endocrine tumors. Furthermore, our investigation also demonstrates that menin-null mESCs can be differentiated in vitro into islet-like endocrine cells, underscoring the utility of menin-null mESC-derived specialized cell types for genome-wide high-throughput studies

Characterisation of prostate cancer lesions in heterozygous Men1 mutant mice

<p>Abstract</p> <p>Background</p> <p>Mutations of the <it>MEN1 </it>gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome. Our group and others have shown that <it>Men1 </it>disruption in mice recapitulates MEN1 pathology. Intriguingly, rare lesions in hormone-dependent tissues, such as prostate and mammary glands, were also observed in the <it>Men1 </it>mutant mice.</p> <p>Methods</p> <p>To study the occurrence of prostate lesions, we followed a male mouse cohort of 47 <it>Men1</it>^+/-mice and 23 age-matched control littermates, starting at 18 months of age, and analysed the prostate glands from the cohort.</p> <p>Results</p> <p>Six <it>Men1</it>^+/-mice (12.8%) developed prostate cancer, including two adenocarcinomas and four <it>in situ </it>carcinomas, while none of the control mice developed cancerous lesions. The expression of menin encoded by the <it>Men1 </it>gene was found to be drastically reduced in all carcinomas, and partial LOH of the wild-type <it>Men1 </it>allele was detected in three of the five analysed lesions. Using immunostaining for the androgen receptor and p63, a basal epithelial cell marker, we demonstrated that the menin-negative prostate cancer cells did not display p63 expression and that the androgen receptor was expressed but more heterogeneous in these lesions. Furthermore, our data showed that the expression of the cyclin-dependent kinase inhibitor CDKN1B (p27), a <it>Men1 </it>target gene known to be inactivated during prostate cell tumorigenesis, was notably decreased in the prostate cancers that developed in the mutant mice.</p> <p>Conclusion</p> <p>Our work suggests the possible involvement of <it>Men1 </it>inactivation in the tumorigenesis of the prostate gland.</p

Caractérisation des modèles murins pour le gène de prédisposition aux Néoplasies Endocrines Multiples de type 1 (étude du rôle de MEN 1 au cours des processus de tumorigenèse liée à son inactivation et du développement du pancréas endocrine)

Le gène MEN1 est un suppresseur de tumeur dont l'inactivation conduit aux Néoplasies Endocrines Multiples de type 1 (NEM1). Pour mieux comprendre son rôle biologique et les conséquences de son inactivation, notre groupe a généré plusieurs modèles murins où ce gène est invalidé. Durant ma thèse, j'ai utilisé l'approche globale des puces oligonucléotidiques pour étudier l'altération de l'expression génique des insulinomes développés par nos souris knockout conditionnel ciblant les cellules b pancréatiques. Mes résultats ont notamment démontré une implication précoce des facteurs génétiques (cycline A2, B2 et D2, IGF-II...) et épigénétiques (méthylation du promoteur d'IGF-II) dans le processus tumoral. Parallèlement, mon travail m'a permis de révéler que le gène Men1 joue un rôle essentiel dès le début du développement du pancréas endocrine chez la souris. L'ensemble des résultats permettra de mieux comprendre les mécanismes de la tumorigenèse des cellules b liée à l'inactivation de MEN1LYON1-BU.Sciences (692662101) / SudocSudocFranceF

Role of cytology in the conservative management of rectal and anal carcinomas

Pour le clinicien confronté au problème du traitement conservateur par irradiation des malades porteurs d'un cancer rectal ou anal, la cytologie peut prendre une place de choix au cours de la surveillanc

Principes d'un essai thérapeutique en oncogériatrie (élaboration d'un protocole d'idarubicine en administration orale dans le cancer de prostate hormonorésistant du sujet âgé)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Distortion Free Wafer Bonding Technology for Backside Illumination Image Sensors

Significant distortion can originate during the bonding process, resulting in overlay issues for final backside illumination image sensor wafer processing, impacting final wafer yield and device reliability. This paper presents a distortion free bonding process where the bonding initiation is controlled by low gas pressure. No external force is needed to initiate the bonding. The resulting overlay capability enables the backside illumination image sensor technical roadmap. In addition, a wafer shape analysis methodology developed for early distortion detection is discussed, allowing bonding process optimization and diagnostic for bonding rework.</jats:p

Distortion Free Wafer Bonding Technology for Backside Illumination Image Sensors

Abstract not Available.</jats:p