Chen Qing, McNinch Colton, May Eve, LaPoint Phoebe, Koroleva Galina, Sutton Ashleigh, Prasad Ruhika, Jo Diana, O'Laughlin Brynn, Patel Anal, Levy Shira, Hourigan Suchitra
Clinical Microbiome Unit, Laboratory of Host Immunity and Microbiome, Division of Intramural Research National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States.
Bioinformatics and Computational Biosciences Branch National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States.
medRxiv. 2025 Apr 22:2025.04.21.25326010. doi: 10.1101/2025.04.21.25326010.
Crohn's disease (CD) is an autoimmune condition with inflammation of the gastrointestinal tract. The etiology of CD is complex with underlying mechanisms only partially elucidated. Retrotransposons, a category of transposable elements within a genome, have been shown to contribute to the pathogenesis of inflammatory and autoimmune disorders. This research aimed to explore the expression of retrotransposons in children with CD.
To assess the expression level of retrotransposons, high-throughput expression analysis at the locus level was performed including LINE, SINE, and LTR-retrotransposons (human endogenous retroviruses (HERVs)) in total RNAseq of ileal and rectal biopsies from treatment-naïve children with CD and age-matched non-Inflammatory Bowel Disease (IBD) controls (CMU-dataset). Findings were validated in public datasets (GSE57945 Ileal; GSE117993 Rectal) from the pediatric RISK study.
Consistent separation of retrotransposon expression between CD and non-IBD controls in both the CMU-dataset and the RISK-dataset was observed in ileal biopsies, but less so in rectal biopsies. In total, 118 differentially expressed retrotransposon loci were identified (27 upregulated and 91 downregulated; 74 LINE-1 and 44 HERV) in CMU-ileal dataset. Fifteen retrotransposon loci were consistently downregulated in both datasets (CMU-ileal and GSE57945): HERV9N-int, HERV9-int (2 loci), HERVH-int (2 loci), HERVK22-int, LTR5A, HERVK-int, L1PA4 (5 loci), L1PA6, L1PA14.
Retrotransposon transcriptome in children with CD significantly differed from non-IBD controls in ileal biopsies with 15 retrotransposon loci consistently downregulated in CD. The possible regulatory function of these retrotransposon loci merits additional research. This study may provide valuable perspectives for the advancement of novel therapeutic strategies.
克罗恩病（CD）是一种伴有胃肠道炎症的自身免疫性疾病。CD的病因复杂，其潜在机制仅部分得到阐明。逆转录转座子是基因组内的一类可移动元件，已被证明与炎症性和自身免疫性疾病的发病机制有关。本研究旨在探讨逆转录转座子在CD患儿中的表达情况。
为评估逆转录转座子的表达水平，对未经治疗的CD患儿和年龄匹配的非炎症性肠病（IBD）对照（CMU数据集）的回肠和直肠活检组织的总RNA进行测序，在基因座水平进行高通量表达分析，包括长散在核元件（LINE）、短散在核元件（SINE）和长末端重复序列逆转录转座子（人类内源性逆转录病毒（HERV））。研究结果在儿科RISK研究的公共数据集（GSE57945回肠；GSE117993直肠）中得到验证。
在CMU数据集和RISK数据集中，回肠活检组织中CD组和非IBD对照组之间的逆转录转座子表达存在一致的分离，但在直肠活检组织中分离程度较小。在CMU回肠数据集中，共鉴定出118个差异表达的逆转录转座子基因座（27个上调和91个下调；74个LINE-1和44个HERV）。在两个数据集（CMU回肠和GSE57945）中，有15个逆转录转座子基因座持续下调：HERV9N-int、HERV9-int（2个基因座）、HERVH-int（2个基因座）、HERVK22-int、LTR5A、HERVK-int、L1PA4（5个基因座）、L1PA6、L1PA14。
CD患儿回肠活检组织中的逆转录转座子转录组与非IBD对照组有显著差异，15个逆转录转座子基因座在CD中持续下调。这些逆转录转座子基因座的潜在调控功能值得进一步研究。本研究可能为新型治疗策略的发展提供有价值的观点。
