Newly identified long noncoding RNA variant may be linked to celiac disease risk

from Healio.com –

Researchers have identified a previously unrecognized long noncoding RNA, lnc13, that may play a role in the intestinal inflammation associated with celiac disease, according to new research published in Science.

“We don’t know why only a fraction of individuals with genetic risk factors for celiac disease actually become gluten intolerant,” Peter H. R. Green, MD, the Phyllis and Ivan Seidenberg Professor of Medicine at Columbia University Medical Center, and director of Celiac Disease Center at Columbia University, said in a press release. “It is only through the dedicated work of translational scientists that we can begin to uncover the mechanisms that unleash the symptoms of celiac disease.”

Recent studies have suggested that long noncoding RNA (lncRNA) may contribute to autoimmune diseases and cancers by interacting with other RNA, DNA and proteins, but it is unclear whether changes in lncRNA genes affect disease risk the way changes in protein-coding genes do, according to the press release.

Therefore, Green and colleagues performed a series of experiments analyzing mouse and human tissues, and found that lnc13 harbors a haplotype block associated with celiac disease and regulates expression of a subset of inflammatory genes associated with celiac disease by interacting with chromatin and hnRNPD, a multifunctional protein. The variant of lnc13 associated with celiac disease binds poorly to these proteins and results in greater expression of inflammatory genes. They also found that levels of lnc13 were significantly reduced in biopsy samples from the small intestines of patients with celiac disease, which they concluded indicates that lnc13 downregulation could contribute to celiac-associated inflammation.

“We believe that lnc13 plays a role in the maintenance of intestinal mucosal immune homeostasis and that dysregulation of lnc13 expression and function — as a result of decapping and genetic polymorphisms, respectively — contributes to inflammation in autoimmune disorders such as [celiac disease],” they wrote.

“These findings add an important detail to our understanding about how celiac disease develops,” Sankar Ghosh, PhD, the Silverstein and Hutt Family Professor of Microbiology and Immunology, and chairman of the department of microbiology and immunology at Colombia University Medical Center, said in the press release. “Given that the majority of the population consumes [gluten-containing] grains, understanding the factors that put certain individuals at greater risk for the development of celiac disease will have a broad impact. In future studies, we hope to investigate factors that lead to suppression of lnc13, which may cause celiac disease in people who were previously able to tolerate gluten.” – by Adam Leitenberger

Lnc13 regulates a subset of CeD-related inflammatory genes

lncRNA

(A) Heat map of the differential expression of a cluster of NF-κB–regulated genes that exhibit expression kinetics highly correlated with lnc13 expression kinetics in response to LPS stimulation (correlation coefficient R > 0.8) of BMDMs. (B) Celiac disease patients present significantly higher levels of the coexpressed genes indicated in (A), as measured by reverse transcription (RT)–QPCR. Horizontal lines represent average values; white rectangles span the 25th and 75th percentile in each group. **P < 0.01, *P < 0.05, +P = 0.05; unpaired t test. (C) Immortalized macrophage cell line stably overexpressing lnc13 by a retroviral pBabe-puro vector shows decreased expression of target genes. Data represent the average and SE of four independent experiments. **P < 0.01, *P < 0.05, +P ≤ 0.1; unpaired t test. (D) Immortalized macrophages show lower levels of lnc13 after transfection of custom small interfering RNAs, using the HiPerfect reagent. Lower lnc13 levels result in increased expression of the target genes. Data represent the average and SE of four independent experiments. **P < 0.01, *P < 0.05, +P ≤ 0.1; unpaired t test.

Disclosure: This study was supported by a research fellowship from the Basque government (Spain), and grants from the Basque Department of Health, the Spanish Instituto de Salud Carlois III, and the NIH.

Source – Healio.com

Castellanos-Rubio A, Fernandez-Jimenez N, Kratchmarov R, Luo X, Bhagat G, Green PH, Schneider R, Kiledjian M, Bilbao JR, Ghosh S. (2016) A long noncoding RNA associated with susceptibility to celiac disease. Science. 352(6281):91-5. [abstract]

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