Genetic and Epigenetic Association of Hepatocyte Nuclear Factor-1α with Glycosylation in Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a complex trauma-related disorder, the etiology and underlying molecular mechanisms of which are still unclear and probably involve different (epi)genetic and environmental factors. Protein N- glycosylation is a common post-translational modification that has been associated with several pathophysiological states, including inflammation and PTSD. Hepatocyte nuclear factor-1α (HNF1A) is a transcriptional regulator of many genes involved in the inflammatory processes, and it has been identified as master regulator of plasma protein glycosylation. The aim of this study was to determine the association between N-glycan levels in plasma and immunoglobulin G, methylation at four CpG positions in the HNF1A gene, HNF1A antisense RNA 1 (HNF1A-AS1), rs7953249 and HNF1A rs735396 polymorphisms in a total of 555 PTSD and control subjects. We found significant association of rs7953249 and rs735396 polymorphisms, as well as HNF1A gene methylation at the CpG3 site, with highly branched, galactosylated and sialyated plasma N-glycans, mostly in patients with PTSD. HNF1A-AS1 rs7953249 polymorphism was also associated with PTSD ; however, none of the polymorphisms were associated with HNF1A gene methylation. These results indicate a possible regulatory role of the investigated HNF1A polymorphisms with respect to the abundance of complex plasma N-glycans previously associated with proinflammatory response, which could contribute to the clinical manifestation of PTSD and its comorbiditie

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases

ORGANISATION DU GENOME ET RELATIONS EVOLUTIVES ENTRE QUELQUES ESPECES DU GENRE QUERCUS

LES ANALYSES DE DIVERSITE, AINSI QUE LES ETUDES D'ECOLOGIE MOLECULAIRE, MENEES SUR LES CHENES ONT CLAIREMENT MIS EN EVIDENCE LA COMPLEXITE SYSTEMATIQUE AU SEIN DU GENRE QUERCUS. COMME DANS BEAUCOUP DE COMPLEXES D'ESPECES LA DELIMITATION BIOLOGIQUE DES ESPECES N'EST PAS TRANCHEE. EN EFFET, DES INTROGRESSIONS ET DE FLUX DE GENES IMPORTANTS ENTRE ESPECES ONT ETE DECRITS. CEPENDANT, MALGRE LES FLUX DE GENES, LA DIFFERENCIATION AU NIVEAU MORPHOLOGIQUE ENTRE ESPECES RESTE VALIDE. AINSI, ON PEUT CITER UNE ABSENCE REMARQUABLE DE COINCIDENCE ENTRE LA DIFFERENCIATION AU NIVEAU PHENOTYPIQUE ET LA DIFFERENCIATION AU NIVEAU GENETIQUE. CETTE ETUDE EST UNE CONTRIBUTION A LA COMPREHENSION DE LA DIFFERENCIATION INTERSPECIFIQUE ET DES RELATIONS PHYLOGENETIQUES AU SEIN DE CE GENRE. ELLE EST BASEE SUR L'ANALYSE DE L'ORGANISATION DU GENOME AU NIVEAU CHROMOSOMIQUE AINSI QU'AU NIVEAU MOLECULAIRE. UN PANEL DE ONZE ESPECES REPRESENTATIVES DES DIFFERENTS GROUPES PHYLOGENETIQUES ET GEOGRAPHIQUES A ETE ANALYSE. UNE ORGANISATION TRES CONSERVEE DES MARQUEURS D'EVOLUTION CHROMOSOMIQUE (L'HETEROCHROMATINE ET LES GENES RIBOSOMIQUES) A ETE REVELE TOUT EN CONFIRMANT UNE STABILITE CARYOTYPIQUE (LES CARACTERES MORPHOLOGIQUES DES CHROMOSOMES) ET GENOMIQUE (TAILLE DU GENOME) AU SEIN DU GENRE. CETTE REMARQUABLE UNIFORMITE CHROMOSOMIQUE CONSTITUE UN BON EXEMPLE DE SPECIATION SANS REARRANGEMENTS CHROMOSOMIQUES IMPORTANTS. UNE DIFFERENCIATION INTERSPECIFIQUE A ETE RECHERCHEE AU NIVEAU MOLECULAIRE ENTRE DEUX CHENES, Q. ROBUR ET Q. SUBER, EN COMPARANT LEURS GENOMES PAR LA TECHNIQUE REPRESENTATIONAL DIFFERENCE ANALYSIS. DES SEQUENCES DIVERGENTES ENTRE LES DEUX ESPECES APPARTIENNENT A LA FRACTION REPETEE DISPERSEE DU GENOME LIEE AUX RETROTRANSPOSONS. LES RESULTATS FONT L'OBJET D'INTERPRETATION SE PLACANT RESOLUMENT DANS LA POLEMIQUE AUTOUR DE LA SPECIATION DANS LE GENRE QUERCUS. AU-DELA DES RESULTATS RELATIFS A LA DIFFERENCIATION GENOMIQUE, UNE PARTIE DE LA THESE ETUDIE LE POLYMORPHISME DES REGIONS D'ORGANISATEURS NUCLEOLAIRES (NORS), OU SE SITUENT LES GENES CODANT POUR L'ARNR 18S-26S. L'ORIGINE DE LA VARIATION DE LA TAILLE DU NOR EST DUE A LA DECONDENSATION DE LA CHROMATINE RIBOSOMIQUES. L'ETUDE DU DEGRE DE DECONDENSATION NOUS A PERMIS DE SUGGERER UN MODELE D'ORGANISATION STRUCTURALE DE CE LOCUS, ET DE DISCUTER LA DYNAMIQUE DE L'ACTIVITE TRANSCRIPTIONNELLE. ON A SUGGERE QUE LE COMPORTEMENT DE LA CHROMATINE RIBOSOMIQUE DE CE LOCUS CORRESPOND AU MECANISME DE COMPACTION DE LA CHROMATINE NECESSAIRE POUR L'INACTIVATION.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Evolutionary implications of heterochromatin and rDNA in chromosome number and genome size changes during dysploidy: A case study in Reichardia genus.

In this study we showed that constitutive heterochromatin, GC-rich DNA and rDNA are implicated in chromosomal rearrangements during the basic chromosome number changing (dysploidy) in Reichardia genus. This small Mediterranean genus comprises 8-10 species and presents three basic chromosome numbers (x = 9, 8 and 7). To assess genome evolution and differentiation processes, studies were conducted in a dysploid series of six species: R. dichotoma, R. macrophylla and R. albanica (2n = 18), R. tingitana and R. gaditana (2n = 16), and R. picroides (2n = 14). The molecular phylogeny reconstruction comprised three additional species (R. crystallina and R. ligulata, 2n = 16 and R. intermedia, 2n = 14). Our results indicate that the way of dysploidy is descending. During this process, a positive correlation was observed between chromosome number and genome size, rDNA loci number and pollen size, although only the correlation between chromosome number and genome size is still recovered significant once considering the phylogenetic effect. Fluorescent in situ hybridisation also evidenced changes in number, position and organisation of two rDNA families (35S and 5S), including the reduction of loci number and, consequently, reduction in the number of secondary constrictions and nuclear organising regions from three to one per diploid genome. The potential mechanisms of chromosomal and genome evolution, strongly implicating heterochromatin, are proposed and discussed, with particular consideration for Reichardia genus

DNA content and GC percentage of <i>Reichardia</i> species from different populations.

<p>DNA content and GC percentage of <i>Reichardia</i> species from different populations.</p

Karyological, cytogenetic and pollen traits plotted on the <i>Reichardia</i> phylogeny.

<p>Posterior probabilities are indicated on branches.</p

Number and distribution of CMA⁺ bands in diploid chromosome set.

<p>Number and distribution of CMA⁺ bands in diploid chromosome set.</p

Number and position of 35S and 5S rDNA loci.

<p>Number and position of 35S and 5S rDNA loci.</p

Hypothetical schema of overarching karyotype evolution in the genus <i>Reichardia</i> involving heterochromatin, rDNA and genome size changes during descending dysploidy.

<p>Hypothetical schema of overarching karyotype evolution in the genus <i>Reichardia</i> involving heterochromatin, rDNA and genome size changes during descending dysploidy.</p