Human molecular genetics · 2026
Multi-omics investigation of thyroid development and dysfunction in down syndrome.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Lauffer Peter, Zwaveling-Soonawala Nitash, Li Yim Andrew Y F, van der Laan Liselot, van Zelderen-Bhola Shama, Venema Andrea M, Mul Adri N, Bugiani Marianna, Siteur-van Rijnstra Esther, Gunst Quinn D, van den Hoff Maurice J B, de Bakker Bernadette S, Boelen Anita, Henneman Peter, van Trotsenburg A S Paul
Аннотация
BACKGROUND: Down syndrome (DS), caused by trisomy of chromosome 21, is associated with a high prevalence of congenital non-autoimmune thyroid dysfunction, typically characterized by an elevated serum thyroid stimulating hormone (TSH) concentration. Early-life observational studies and fetal cordocentesis data, consistently reporting elevated TSH levels, suggest a developmental origin. However, the underlying pathophysiological mechanism remains unclear. This study aimed to investigate the molecular and developmental features underlying thyroid dysfunction in DS.
METHODS: Thyroid tissue of fetuses with DS (n = 4) and fetuses without a genetic/developmental abnormality (n = 5) were analyzed using histology, bulk RNA sequencing (RNA-seq), and DNA methylation (DNAm) profiling.
RESULTS: Histological analysis revealed underdevelopment of DS fetal thyroid tissue, with smaller follicles and greater heterogeneity. RNA-seq identified 1035 differentially expressed genes (DEGs) distributed across the genome. Notably, three thyroid-relevant genes, FOXE1, IYD, and DIO2, were significantly downregulated in DS tissue. Gene set enrichment analysis (GSEA) showed widespread disruption of cellular processes. DNAm analysis identified 266 differentially methylated regions (DMRs), several of which overlapped with loci previously implicated in DS. Integration of expression and DNAm data revealed 20 significant integrative methylation-expression analysis associations, indicating cis-regulatory DNAm effects on gene expression.
CONCLUSIONS: These findings suggest that congenital thyroid dysfunction in DS represents a DS-specific form of thyroid dysfunction, characterized by impaired thyroid development and altered expression and regulation of genes involved in thyroid function and general cellular processes. The genome-wide molecular changes observed likely result from gene dosage effects and systemic (epi)genomic disturbances caused by trisomy 21.
METHODS: Thyroid tissue of fetuses with DS (n = 4) and fetuses without a genetic/developmental abnormality (n = 5) were analyzed using histology, bulk RNA sequencing (RNA-seq), and DNA methylation (DNAm) profiling.
RESULTS: Histological analysis revealed underdevelopment of DS fetal thyroid tissue, with smaller follicles and greater heterogeneity. RNA-seq identified 1035 differentially expressed genes (DEGs) distributed across the genome. Notably, three thyroid-relevant genes, FOXE1, IYD, and DIO2, were significantly downregulated in DS tissue. Gene set enrichment analysis (GSEA) showed widespread disruption of cellular processes. DNAm analysis identified 266 differentially methylated regions (DMRs), several of which overlapped with loci previously implicated in DS. Integration of expression and DNAm data revealed 20 significant integrative methylation-expression analysis associations, indicating cis-regulatory DNAm effects on gene expression.
CONCLUSIONS: These findings suggest that congenital thyroid dysfunction in DS represents a DS-specific form of thyroid dysfunction, characterized by impaired thyroid development and altered expression and regulation of genes involved in thyroid function and general cellular processes. The genome-wide molecular changes observed likely result from gene dosage effects and systemic (epi)genomic disturbances caused by trisomy 21.