La croissance fœtale est un processus complexe dépendant de facteurs génétiques, environnementaux, nutritionnels et hormonaux d’origine maternelle, placentaire et fœtale. Le système IGF est l’un des systèmes hormonaux les plus importants pour la régulation de la croissance fœtale et placentaire [1]. Le gène IGF-II est régulé par le phénomène d’empreinte parentale et est exprimé seulement à partir de l’allèle paternel dans la majorité des tissus pendant la vie fœtale. Les gènes soumis à empreinte parentale sont régulés de manière spécifique et sont particulièrement vulnérables aux signaux environnementaux et nutritionnels. La dérégulation d’un groupe de gènes de la région 11p15 soumise à empreinte parentale, incluant le gène IGF-II, est responsable de deux pathologies de croissance fœtale (les syndromes de Silver-Russell, OMIM 180860 et de Wiedemann-Beckwith, OMIM 130650) qui ont une présentation phénotypique opposée. Ces deux syndromes représentent d’excellents modèles de pathologies humaines pour l’étude de la régulation de l’empreinte parentale. arabic 9 English 26
- Demars, J , S. Rossignol, Mansur Ennuri Moftah Shmela, I. Netchine, S. Azzi, A. El-Osta, Y. Le Bouc, C. Gicquel(1-2012)

Formaldehyde is an anxious gas used as a tissue preservative of cadavers in anatomy halls. Therefore, laboratory staff and students are at high risk of different clinical complications due to the continuous exposure to formaldehyde. The present questionnaire-based study evaluates the effects of formaldehyde exposure on veterinary students and staff in the anatomy gross dissection laboratory, University of Tripoli, Libya. A total of 104 students and 6 anatomy staff members completed a questionnaire of 24 questions related to the clinical symptoms observed after formaldehyde exposure and the answers were assessed using a six point (0-5) scale. Students had a high prevalence of nasal itching 78(75%), eyes burning 78(75%), excessive lacrimation 76(73%), eyes redness 60(58%), headache 64(62%) and respiratory distress 61(59%). Smoking and wearing glasses or gloves worsened many symptoms while wearing masks minimized other symptoms and male students were more affected than females. All anatomy staff members (100%) reported nasal itching, burning and congestion, eyes burning and redness, excessive lacrimation, cough and respiratory distress and less than that (83%) suffered from mouth dryness, headache, temporary loss of their ability to recognize the smell of formaldehyde and needed a physician assistance after the exposure to formaldehyde. The repeated exposure to formaldehyde in gross anatomy dissection has harmful effects on both students and staff member and finding alternative preservation methods, such as freezing, would be safer than using the formaldehyde. arabic 12 English 74
Fahima A Alnagar, Mansur Ennuri Moftah Shmela, , Abdulrhman Mohamed Salah Alrtib, , Fathia mahmoud Mohammad Ashour, Amal Omar Elarif Buker, Anwar Mustafa Abdalhadi Abdalmula(10-2015)

The human 11p15 region is divided into two independent imprinted domains, the H19/IGF2 and CDKN1C/KCNQ1 domains. Each domain is regulated by its own imprinting control regions, ICR1 and ICR2, which carry opposite germline imprints. The expression of 11p15 imprinted genes is regulated by two major mechanisms. ICR1 binds a zinc finger protein (CTCF) on the unmethylated maternal allele and acts as a chromatin insulator, whereas ICR2 is unmethylated on the paternal allele and serves as a promoter for a regulatory non-coding RNA (KCNQ1OT1). Dysregulation of 11p15 genomic imprinting results in two human foetal growth disorders: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes, which display opposite growth phenotypes. Various 11p15 epigenetic and genetic defects result in BWS and SRS. Gain or loss of DNA methylation account for 60% of BWS and SRS and, in most cases, the mechanism of the DNA methylation defect is unknown. The overall aim of this thesis was to decipher the mechanisms resulting in loss or gain of DNA methylation at ICR1 or ICR2 by investigating large cohorts of BWS and SRS patients displaying a “primary” DNA methylation defect. We aimed at establishing what was the incidence of copy number variations (CNVs) (duplications, deletions and segmental uniparental isodisomies) confined to one or one part of the H19/IGF2 or CDKN1C/KCNQ1 domains. We also screened extensively the ICR1 imprinting control region in BWS and SRS patients to identify new genetic defects. We show in this work that genetic defects in cis account for a significant proportion (approximately 30%) of BWS patients with ICR1 gain of DNA methylation but are rare in SRS and BWS patients with loss of DNA methylation at ICR1 and ICR2, respectively. We describe novel small gain and loss CNVs involving only part of the two domains in BWS and SRS. We also describe, for the first time, mutations and small deletions involving binding sites for the OCT4 and SOX2 pluripotency factors. Those defects account for approximately 14% of BWS cases and result in a BWS phenotype upon maternal transmission. We further characterize the role of OCT4/SOX2 pluripotency factors in the maintenance of genomic imprinting at the H19/IGF2 domain in mouse embryonic stem cells. By screening the whole 11p15 region for susceptibility alleles for loss or gain of DNA methylation, our group identified a novel 4.5 kb cis-regulatory region within the CDKN1C/KCNQ1 domain. A specific 4.5 kb haplotype confers, upon maternal transmission, a risk of ICR2 loss of DNA methylation in BWS patients. This study investigated the mechanism involved in the risk of ICR2 loss of DNA methylation in BWS and showed that within this 4.5 kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20 bp core motifs. This study identifies a new cis-regulatory region and highlights the crucial role of CTCF for the regulation of genomic imprinting at the CDKN1C/KCNQ1 domain. These recent findings bring new insights in the regulation of genomic imprinting at both the IGF2/H19 and CDKN1C/KCNQ1 domains. arabic 8 English 50
Mansur Ennuri Moftah Shmela(9-2014)