Role of DNA methylation in common disease: analysis of two asthma-associated regions
Notice bibliographique
Résumé
Two chromosomal regions, 5q31 and 17q21, are both among the best replicated asthma-associated regions from genome-wide association studies (GWAS) and share certain characteristics.They are among the highest genome-wide significance allele-specific expression differences: in the 17q region, the childhood asthma-associated allele shows increased expression of gasdermin B (GSDMB) and ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) genes and in the 5q31 region the asthma-associated allele shows increased expression of the solute carrier family 22 (organic 3 cation/carnitine transporter) member 5 (SLC22A5) genes. This suggests that cis-regulatory mechanisms may influence disease development in these regions. Among children, the prevalence of asthma is higher in boys than girls, 5q31 and 17q21 regions show sex specificity of genetic association: the association with asthma is stronger in males than females, and both are associated with several autoimmune disorders such as asthma and Crohn’s disease, among different populations. We hypothesize that variation in DNA methylation at regulatory elements within asthma-associated genomic regions 5q31 and 17q21 may acts as a modifier of the effect of genotype on phenotype. To better understand the relationship between genetic variation in these regions, DNA methylation, and predisposition to asthma, we established DNA methylation profiles of 13 genes. We used sodium bisulfite sequencing methylation assay to examine the effects that genotype has on DNA methylation in the peripheral blood cells from individuals in the Saguenay-Lac-Saint-Jean (SLSJ) asthma familial collection and lymphoblastoid cell lines (LCLs). We found a single regulatory region, the zona pellucida binding protein 2 (ZPBP2) promoter, which showed a statistically significantly higher methylation level in females compared to males. The local genotype influenced methylation levels of SLC22A5, ZPBP2 and gasdermin A (GSDMA) promoter regions. The genotype had a dominant effect on SLC22A5, ZPBP2 and GSDMA methylation, with lower methylation levels in individuals that carry the asthma-predisposing alleles. To understand whether the moderate change in DNA methylation leads to a change in gene expression levels in 5q31 and 17q21, the effect of treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) on expression and promoter methylation of genes in 5q31 and 17q21 in the human airway epithelium cell line, NuLi-1 and embryonic kidney epithelium cell line, HEK293T/17 was assessed. We found that SLC22A5 and GSDMA were upregulated after 5-aza-dC treatment in both cell lines. ZPBP2 expression was increased in NuLi-1 but remained silent in HEK293T/17, while ORMDL3 showed upregulation in HEK293T/17 but not NuLi-1. Increased2expression of ZPBP2 and GSDMA was accompanied by a reduction in promoter methylation, whereas no change in SLC22A5 promoter methylation levels was observed. Furthermore, we noticed modification in allelic expression of ZPBP2 and ORMDL3, suggesting that each region may react in uniquely to 5-aza-dC.We hypothesized that sex-specific differences in DNA methylation levels at the ZPBP2 promoter resulted from the dosage of the sex chromosomes. Thus, ZPBP2 DNA methylation was analyzed using the sodium bisulfite sequencing assay in DNA samples from fibroblast cell lines derived from individuals with different sex phenotypes and sex chromosome dosages. No significant influence of the sex phenotype was detected. However, a significant positive correlation was found between ZPBP2 methylation levels and the number of X chromosomes. Our results suggest that the presence of more than one X in the absence of the sex-determining region Y (SRY) gene is associated with higher methylation levels.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».