MicroRNA-mediated Regulation of Mucin-type O-glycosylation Pathway: A Putative Mechanism of Salivary Gland Dysfunction in Sjögren Syndrome

Gallo, Alessia; Vella, Serena; Tuzzolino, Fabio; Cuscino, Nicola; Cecchettini, Antonella; Ferro, Francesco; Mosca, Marta; Alevizos, Ilias; Bombardieri, Stefano; Conaldi, Pier Giulio; Baldini, Chiara

doi:10.3899/jrheum.180549

Cited by 10 publications

(8 citation statements)

References 39 publications

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“…Conversely, shared downregulated genes showed enrichment in processes associated with O-glycan processing, ER to Golgi vesicle-mediated transport, carbohydrate metabolic process, and protein N-linked glycosylation via asparagine ( Supplementary Figure S5 and Supplementary Table S8 ). Interestingly, the observed downregulation of genes important for normal glycan function is in good agreement with the suggested role glycans play in influencing salivary flow, which is commonly reduced in pSS patients ( 68 ).…”

Section: Resultssupporting

confidence: 83%

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

et al. 2021

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Sjögren’s Syndrome (SS) is a chronic autoimmune disease of unknown etiology which primarily affects the salivary and lacrimal glands resulting in the loss of secretory function. Treatment options for SS have been hampered due to the lack of a better understanding of the underlying gene regulatory circuitry and the interplay between the myriad pathological cellular states that contribute to salivary gland dysfunction. To better elucidate the molecular nature of SS, we have performed RNA-sequencing analysis of the submandibular glands (SMG) of a well-established primary Sjögren’s Syndrome (pSS) mouse model. Our comprehensive examination of global gene expression and comparative analyses with additional SS mouse models and human datasets, have identified a number of important pathways and regulatory networks that are relevant in SS pathobiology. To complement these studies, we have performed single-cell RNA sequencing to examine and identify the molecular and cellular heterogeneity of the diseased cell populations of the mouse SMG. Interrogation of the single-cell transcriptomes has shed light on the diversity of immune cells that are dysregulated in SS and importantly, revealed an activated state of the salivary gland epithelial cells that contribute to the global immune mediated responses. Overall, our broad studies have not only revealed key pathways, mediators and new biomarkers, but have also uncovered the complex nature of the cellular populations in the SMG that are likely to drive the progression of SS. These newly discovered insights into the underlying molecular mechanisms and cellular states of SS will better inform targeted therapeutic discoveries.

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Section: Resultssupporting

confidence: 83%

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

et al. 2021

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“…In LSG from SS-patients with LFS compared to sicca controls, we found 3 miRNAs differentially expressed (hsa-miR-769-5p, hsa-miR-493-5p and hsa-miR-181d-5p), implicated in regulating 4 genes encoding for glycosyltransferases of the Golgi apparatus involved in mucin O-Glycan biosynthesis (POC1B-GALNT4, GALNT4, GALNT10 and C1GALT1) (Supplementary Table S3). This observation (Table 2) is in agreement with a previous report connecting this miRNA to the downregulation of GALNT4 ( 61), a member of the GalNAc-T family of enzymes which initiates Oglycosylation of mucins in epithelial cells, a process that is altered in SS-patients (23,61). The downregulation on hsa-miR-769-5p observed in LSG from SS-patients with HFS compared to SSpatients with LFS (Table 2) may be a consequence of the loss of the epithelial component and its replacement by inflammatory cells in the LSG from SS-patients with HFS.…”

Section: Functional Enrichment Analysis Of Differentially Expressed M...supporting

confidence: 92%

Small RNA Expression Profiling Reveals hsa-miR-181d-5p Downregulation Associated With TNF-α Overexpression in Sjögren’s Syndrome Patients

et al. 2022

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MicroRNAs (miRNAs) are small non-coding RNAs (sRNA), that alter gene expression by binding to target messenger RNAs (mRNAs) and repressing translation. Dysregulated miRNA expression has been implicated in the pathogenesis of autoimmune diseases such as Sjögren’s syndrome (SS). The aim of this study was to characterize the global profile of sRNAs in labial salivary glands (LSG) from SS-patients and to validate potential miRNA candidates implicated in glandular inflammation. LSG from 21 SS-patients and 9 sicca controls were analyzed. A global next generation sequencing (NGS)-based sRNA profiling approach was employed to identify direct targets whereby differentially expressed miRNAs were predicted using bioinformatics tools. miRNA levels were validated by TaqMan and target mRNA levels were determined by quantitative real-time PCR. We also performed in vitro assays using recombinant TNF-α. NGS shows that ~30% of sRNAs were miRNAs. In comparison with samples from sicca controls, four miRNAs were found differentially expressed in LSG from SS-patients with low focus score (LFS) and 18 from SS-patients with high focus score (HFS). The miRNA with the most significant changes identified by NGS was hsa-miR-181d-5p and downregulation was confirmed by TaqMan analysis. Levels of TNF-α mRNA, a direct target of hsa-miR-181d-5p, were significantly increased and negatively correlated with hsa-miR-181d-5p presence. Moreover, positive correlations between TNF-α transcript levels, focus score, ESSDAI, and autoantibody levels were also detected. Furthermore, TNF-α stimulation decreased hsa-miR-181d-5p levels in vitro. Downregulation of hsa-miR-181d-5p in LSG from SS-patients could contribute to the glandular pro-inflammatory environment by deregulation of its direct target TNF-α. Further dissection of the pathophysiological mechanisms underlying the hsa-miR-181d-5p-mediated action in inflammatory conditions could be useful to evaluate the benefits of increasing hsa-miR-181d-5p levels for restoration of salivary gland epithelial cell architecture and function.

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“…Functional annotation of the differently expressed miRNAs showed that the miRNAs target and regulate proteins that are involved in salivary secretion and various immune system processes (Table 2), which is reflected in significantly lower UWS and SWS flow rates and more extensive focal lymphocytic infiltration in the pSS group. Dysregulation of some of these pathways, for example, TGF‐β and Mucin‐type O glycosylation, has previously been described in relation to pSS 13,31 . However, interpretation of signaling pathways identified in silico should be done with caution, as some miRNAs are more frequently studied and reported and few signaling pathways have been verified in human oral tissues.…”

Section: Discussionmentioning

confidence: 99%

Distinct microRNA expression profiles in saliva and salivary gland tissue differentiate patients with primary Sjögren's syndrome from non‐Sjögren's sicca patients

Sembler-Møller

Belstrøm

Locht

et al. 2020

J Oral Pathology Medicine

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Objectives Increasing evidence suggests that aberrant expression of microRNAs (miRNAs) is involved in the pathogenesis of primary Sjögren's syndrome (pSS). The aim was thus to characterize the miRNA profile in saliva, salivary gland tissue, and plasma from patients with pSS and compare findings with those of patients having Sjögren‐like disease (non‐pSS). In addition, to correlate miRNA levels and clinicopathological features of pSS. Methods miRNA real‐time quantitative polymerase chain reaction was performed on saliva, plasma, and salivary gland tissue samples from 24 patients with pSS and 16 non‐pSS in 384‐well plates. T test was used for comparison of miRNA profiles, followed by Benjamini‐Hochberg correction. The discriminatory power of miRNAs was evaluated by receiver‐operating characteristic curves, and Pearson/Spearman correlation was used for correlation analyses. Results In saliva, 14 miRNAs were significantly differentially expressed between pSS and non‐pSS, including downregulation of the miR‐17 family in pSS. In salivary gland tissue of patients with pSS, miR‐29a‐3p was significantly upregulated. Plasma miRNAs did not differ between the two groups, although the miR‐17 family tended to be downregulated. The combination of miR‐17‐5p and let‐7i‐5p in saliva yielded an area under curve of 97% (CI 92%‐100%). Several miRNAs correlated significantly with one another and with salivary flow rates and histopathology. Conclusion Our findings indicate that the miRNA expression profile in saliva may enable to discriminate between pSS and non‐pSS patients. However, further validation in larger cohorts is needed as well as functional analyses of the miRNAs of interest.

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MicroRNA-mediated Regulation of Mucin-type O-glycosylation Pathway: A Putative Mechanism of Salivary Gland Dysfunction in Sjögren Syndrome

Cited by 10 publications

References 39 publications

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

Small RNA Expression Profiling Reveals hsa-miR-181d-5p Downregulation Associated With TNF-α Overexpression in Sjögren’s Syndrome Patients

Distinct microRNA expression profiles in saliva and salivary gland tissue differentiate patients with primary Sjögren's syndrome from non‐Sjögren's sicca patients

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