Influence of conception and delivery mode on stress response marker Oct4B1 and imprinted gene expression related to embryo development: A cohort study

Background: Recent scientific data support that the mode of conception and delivery may influence epigenetic regulation and therefore embryo development. Octamer-binding transcription factor 4-B1 (OCT4B1), a novel variant of OCT4 with yet unknown biological function, is suggested to have a potential role in mediating cellular stress response. Furthermore, Insulinlike Growth Factor 2 (IGF2), Mesoderm-specific Transcript (MEST) and paternally expressed gene 10 (PEG10) are genes known as imprinted and are regulated via means of epigenetic regulation. The influence of delivery mode and conception on epigenetic regulation is an active research field. Objective: Our aim was to correlate the expression level of Oct4B1 and the expression and methylation level of IGF2, MEST, and PEG10 imprinted genes with the mode of delivery and conception in the umbilical cord blood of newborns. Materials and Methods: Samples of umbilical cord blood from infants born after vaginal delivery, caesarean section (CS) with the infant in cephalic position and CS due to breech position were examined. Furthermore, the investigation included infants conceived through means of assisted reproductive technology. Results: No statistically significant differences were found in mRNA expression levels between different modes of conception and delivery (p = 0.96). Oct4B1, IGF2, MEST, and PEG10 expression levels do not seem to be significantly affected by different modes of conception and delivery. Conclusion: These results indicate that the expression and methylation patterns of Oct4B1, IGF2, MEST and PEG10 in umbilical cord blood are not affected by the conception and delivery mode. Key words: Conception, Fertilization in vitro, Genomic imprinting, Fetal blood

Stressful Newborn Memories: Pre-Conceptual, In Utero, and Postnatal Events

Early-life stressful experiences are critical for plasticity and development, shaping adult neuroendocrine response and future health. Stress response is mediated by the autonomous nervous system and the hypothalamic–pituitary–adrenal (HPA) axis while various environmental stimuli are encoded via epigenetic marks. The stress response system maintains homeostasis by regulating adaptation to the environmental changes. Pre-conceptual and in utero stressors form the fetal epigenetic profile together with the individual genetic profile, providing the background for individual stress response, vulnerability, or resilience. Postnatal and adult stressful experiences may act as the definitive switch. This review addresses the issue of how preconceptual in utero and postnatal events, together with individual differences, shape future stress responses. Putative markers of early-life adverse effects such as prematurity and low birth weight are emphasized, and the epigenetic, mitochondrial, and genomic architecture regulation of such events are discussed

Αξιολόγηση της χρήσης κορτικοστεροειδών σε παιδιατρικούς ασθενείς με Δευτεροπαθές Αιμοφαγοκυτταρικό Σύνδρομο & Σύνδρομο Ενεργοποίησης Μακροφάγων

Η αιμοφαγοκυτταρική λεμφοϊστιοκυττάρωση είναι ένα όχι συχνό, όμως δυνητικά υπερφλεγμονώδες σύνδρομο, το οποίο κλινικά χαρακτηρίζεται από παρατεταμένο πυρετό, ηπατοσπληνομεγαλία, κυτταροπενίες, υπερτριγλυκεριδαιμία, υπερφερριτιναμία και αιμοφαγοκυττάρωση στον μυελό των οστών, στο ήπαρ, στον σπλήνα ή στους λεμφαδένες. Η παθοφυσιολογία του βασίζεται στην ελλατωματική λειτουργία των κυτταροτοξικών Τ λεμφοκυττάρων, των φυσικών φονικών κυττάρων, καθώς και των μακροφάγων. (1) Το πρωτογενής HLH οφείλεται σε γονιδιακή προδιάθεση που οφείλεται σε διάφορες γενετικές παθήσεις, όπως οικογενές-HLH (fHLH 2-5) (2), σύνδρομο Griscelli τύπου 2, σύνδρομο Chediak-Higashi, διάφορα σύνδρομα αλμπινισμού με ανοσοανεπάρκεια (GS2, CHS, HPS2) (3), λεμφουπερπλαστικά σύνδρομα που σχετίζονται με το χρωμόσωμα Χ (XLP1+2) (4) και άλλοι τύποι. Το HLH προκαλείται κυρίως από λοιμώξεις και η έναρξη του πρωτοπαθούς HLH συμβαίνει συνήθως κατά την παιδική ηλικία, αν και οι αναφορές σχετικά με την παρουσίασή του σε ενήλικες αυξάνονται. (2) Το δευτερογενές ή επίκτητο HLH προκαλείται από ευρύ φάσμα αιτιών, συμπεριλαμβανομένων των: λοιμώξεων, κακοηθειών, αυτοάνοσων νοσημάτων, μεταβολικών νόσων και επίκτητων ανοσολογικών ανεπαρκειών - όπως το AIDS, η ιατρογενής ανοσοκαταστολή και η μεταμόσχευση συμπαγών οργάνων ή αρχέγονων αιμοποιητικών κυττάρων.As an infrequent but potentially life -threatening hyperinflammatory syndrome (HLH) is clinically characterized with prolonged fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, hyperferritinamia, and hemophagocytosis in bone marrow, liver, spleen, or lymph nodes. Its pathophysiology is based on the impaired function of cytotoxic T lymphocytes, and natural killer cells, as well as macrophages. (1) Primary HLH consist of several genetic conditions, including familialHLH (fHLH 2-5) (2), Griscelli syndrome type 2, Chediak-Higashi syndrome, several albinism syndromes with immunodeficiency (GS2, CHS, HPS2) (3) and X-linked lymphoproliferative syndromes (XLP1+2). (4) and other types . HLH is triggered mainly by infections, and the onset of primary HLH usually occurs during childhood, although reports regarding its adult presentation are increasing. (2) Secondary or acquired HLH is caused by a wide range of causes, including infections, malignancies, autoimmune diseases, metabolic diseases and acquired immune deficiencies- such as AIDS, iatrogenic immune suppression and organ or stem cell transplantation

Developmental Dyslexia: Environment Matters

Developmental dyslexia (DD) is a multifactorial, specific learning disorder. Susceptibility genes have been identified, but there is growing evidence that environmental factors, and especially stress, may act as triggering factors that determine an individual’s risk of developing DD. In DD, as in most complex phenotypes, the presence of a genetic mutation fails to explain the broad phenotypic spectrum observed. Early life stress has been repeatedly associated with the risk of multifactorial disorders, due to its effects on chromatin regulation, gene expression, HPA axis function and its long-term effects on the systemic stress response. Based on recent evidence, we discuss the potential role of stress on DD occurrence, its putative epigenetic effects on the HPA axis of affected individuals, as well as the necessity of early and appropriate intervention, based on the individual stress-associated (endo)phenotype

Brief Communication: Variation in the Number of FMRl Microsatellite Repeats in Three Subgroups of the Hellenic Population

Microsatellites have been used for human evolution and origin studies by comparing their frequency, diversity, and allele size. In this study we report the analysis of three microsatellite loci, FMRl CGG and flanking DXS548 and FRAXAC2, in three separate groups of the Hellenic population: Athens, representing the genera] Hellenic population; Epirus (northwest Greece); and Cyprus. Significant variations in frequency and diversity were found in the three groups. Compared with Athens, Epirus had a tendency for longer alleles and a higher heterozygosity for DXS548. Cyprus had a frequency of CGG alleles similar to Athens but a low heterozygosity and a limited number of alleles at DXS548 and FRAXAC2. Allele differences of microsatellite loci not only are present in remote populations but also are evident between groups belonging to the same population. Microsatellite analysis could be a useful tool for identifying the origin of the founder chromosomes in intrapopulation studies and the time elapsed from the establishment of each population subgroup

Mechanical stress affects methylation pattern of GNAS isoforms and osteogenic differentiation of hAT-MSCs

Mechanical stress exerts a substantial role on skeletal-cell renewal systems, whereas accumulating evidence suggests that epigenetic mechanisms induce changes and differential gene expression. Although the underlying mechanisms remain to be fully elucidated, our study suggests that the influence of the long term mechanical stimulation elicits epigenetic modifications controlling osteogenic differentiation of human adipose tissue multipotential stromal cells (hAT-MSCs) and contributes to an accelerating in vitro osteogenesis. GNAS imprinting gene acts as a critical regulator of osteoblast differentiation and is implicated in human genetic disorders with pathological formation of ectopic-skeletal bone. Investigating a wide variety of stimuli, we showed that daily mechanical stretch on hAT-MSCs of 7th and 15th days' intervals induced a significant down-regulation in DNA methylation status of critical CpG sites of NESP and GNASXL isoforms, accompanied by up-regulation of the corresponding gene transcripts, and osteogenic differentiation earlier in culture. Importantly, methylation analysis of differentiating bone marrow-derived MSCs revealed similar methylation patterns. Bioinformatic analysis further showed that all CpG islands exhibiting significant methylation alterations encompassed transcriptional repressor CTCF binding sites. We hereby emphasize the need to investigate the epigenetic alterations on hAT-MSCs during environmental mechanical forces and to consider how the knowledge gained through these studies may foster new means of symptoms prevention and management of ectopic bone formation in the clinic. [Display omitted] •Long-term mechanical cell stretching of hAT-MSCs leads to early osteogenesis induction.•Demethylation ratio of GNAS' CpGs is dependent on the duration of mechanical stress.•Osteo-specific GNAS isoforms' methylation profile is directly associated to CTCF binding factors.•Targeting to promising therapeutic approaches for the pathological ectopic bone formatio

Refining the locus of branchio-otic syndrome 2 (BOS2) to a 5.25 Mb locus on chromosome 1q31.3q32.1

In 1991, a large family was described with an autosomal dominant inheritance of otological and branchial manifestations which was termed branchio-otic syndrome type 2 (BOS2). This trait was mapped by linkage analysis in this family to a region of 23-31 Mb on chromosome 1q25.1q32.1. In the present report we describe the clinical features of two patients with a deletion in this region: one patient has a deletion but no otological or branchial manifestations, the other patient manifests mild conductive hearing loss resulting from bilaterally malformed middle ear ossicles, as well as a preauricular pit. Mapping of the deletion breakpoints allowed to delineate the region involved in BOS2 to a 5.25 Mb region containing 27 protein-coding genes. A detailed medical history of both patients is provided and they are compared with the literature on other detected interstitial deletions of 1q25q32. These findings will aid in the identification of the genetic cause underlying BOS2.status: publishe

Refining the locus of branchio-otic syndrome 2 (BOS2) to a 5.25 Mb locus on chromosome 1q31.3q32.1

In 1991, a large family was described with an autosomal dominant inheritance of otological and branchial manifestations which was termed branchio-otic syndrome type 2 (BOS2). This trait was mapped by linkage analysis in this family to a region of 23-31 Mb on chromosome 1q25.1q32.1. In the present report we describe the clinical features of two patients with a deletion in this region: one patient has a deletion but no otological or branchial manifestations, the other patient manifests mild conductive hearing loss resulting from bilaterally malformed middle ear ossicles, as well as a preauricular pit. Mapping of the deletion breakpoints allowed to delineate the region involved in BOS2 to a 5.25 Mb region containing 27 protein-coding genes. A detailed medical history of both patients is provided and they are compared with the literature on other detected interstitial deletions of 1q25q32. These findings will aid in the identification of the genetic cause underlying BOS2. (C) 2009 Published by Elsevier Masson SAS

The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2

Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromosomal rearrangements (CCRs) are associated with local shattering of chromosomal regions (chromothripsis). Although MPS promises to identify the molecular basis of the abnormal phenotypes associated with many CCRs, none of the reported mate-pair sequenced complex rearrangements have been simultaneously studied with state-of-the art molecular cytogenetic techniques. Here, we studied chromothripsis-associated CCR involving chromosomes 2, 5 and 7, associated with global developmental and psychomotor delay and severe speech disorder. We identified three truncated genes: CDH12, DGKB and FOXP2, confirming the role of FOXP2 in severe speech disorder, and suggestive roles of CDH12 and/or DGKB for the global developmental and psychomotor delay. Our study confirmes the power of MPS for detecting breakpoints and truncated genes at near nucleotide resolution in chromothripsis. However, only by combining MPS data with conventional G-banding and extensive fluorescence in situ hybridizations could we delineate the precise structure of the derivative chromosomes