A limited set of transcriptional programs define major cell types

Breschi, Alessandra; Muñoz-Aguirre, Manuel; Wucher, Valentin; Davis, Carrie A.; Garrido-Martín, Diego; Djebali, Sarah; Gillis, Jesse; Pervouchine, Dmitri D.; Vlasova, Anna; Dobin, Alexander; Zaleski, Chris; Drenkow, Jörg; Danyko, Cassidy; Scavelli, Alexandra; Reverter, Ferrán; Snyder, M; Gingeras, T; Guigó, Roderic

doi:10.1101/gr.263186.120

Cited by 30 publications

(23 citation statements)

References 41 publications

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“…Armed with a global view of the overall transcriptional changes in the glands of pSS patients, we next sought to characterize the cell types that may be contributing to the alterations in gene expression. Towards this end we utilized xCell ( 44 ), a cell type enrichment analysis tool that allowed us to estimate the cell types contributing to the bulk RNA-seq expression profile using published information from single-cell RNA-seq datasets ( 66 – 68 ). As expected, we observed enrichment of genes associated with various immune cells types including B cells, conventional dendritic cells (cDC), plasmacytoid dendritic cells (pDC) and CD4 + effector memory T cells (CD4 + Tem) in the pSS glands, which is in good agreement with previous reports ( 69 – 74 ) ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

et al. 2021

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Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized primarily by immune-mediated destruction of exocrine tissues, such as those of the salivary and lacrimal glands, resulting in the loss of saliva and tear production, respectively. This disease predominantly affects middle-aged women, often in an insidious manner with the accumulation of subtle changes in glandular function occurring over many years. Patients commonly suffer from pSS symptoms for years before receiving a diagnosis. Currently, there is no effective cure for pSS and treatment options and targeted therapy approaches are limited due to a lack of our overall understanding of the disease etiology and its underlying pathology. To better elucidate the underlying molecular nature of this disease, we have performed RNA-sequencing to generate a comprehensive global gene expression profile of minor salivary glands from an ethnically diverse cohort of patients with pSS. Gene expression analysis has identified a number of pathways and networks that are relevant in pSS pathogenesis. Moreover, our detailed integrative analysis has revealed a primary Sjögren’s syndrome molecular signature that may represent important players acting as potential drivers of this disease. Finally, we have established that the global transcriptomic changes in pSS are likely to be attributed not only to various immune cell types within the salivary gland but also epithelial cells which are likely playing a contributing role. Overall, our comprehensive studies provide a database-enriched framework and resource for the identification and examination of key pathways, mediators, and new biomarkers important in the pathogenesis of this disease with the long-term goals of facilitating earlier diagnosis of pSS and to mitigate or abrogate the progression of this debilitating disease.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

et al. 2021

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“…The lower replication value in sigmoid colon may be owing to the higher proportion of muscularis in this tissue. 8,35 We found fewer sGenes than eGenes, partly because the number of genes that showed splicing variability was lower than genes with expression variability. In addition, we had lower power to detect expression for transcripts than for genes at our depth of coverage.…”

Section: Q22mentioning

confidence: 83%

“…In contrast to BarcUVa-Seq, the GTEx project provided RNA-Seq data on sigmoid and transverse colon tissue from post-mortem subjects and extracted RNA from fullthickness and muscularis-only sections. 8,35 Our novel BarcUVa-Seq data set overcomes some of the limitations of the GTEx colon data sets. BarcUVa-Seq samples were collected as superficial mucosal biopsy specimens in living subjects undergoing colonoscopy, which provide an optimal representation of the normal physiology of the colon epithelium.…”

Section: Discussionmentioning

confidence: 99%

Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci

Díez-Obrero

Dampier

Moratalla-Navarro

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Colon biopsies from superficial mucosa Gene expression and alternative splicing DNA genotyping eQTLs and sQTLs Blood samples Colon Transcriptome Explorer Enrichment at regulatory regions and trait and diseaseassociated loci Differential expression between colon subsites …ACTGCATGCTACC… SUMMARYWe profiled gene expression and alternative splicing of nonneoplastic colon from biopsy specimens from 445 healthy individuals. We showed that single-nucleotide polymorphisms associated with these profiles are enriched in disease-associated loci, including colorectal cancer and inflammatory bowel disease. BACKGROUND & AIMS:The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource. METHODS:We collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses. RESULTS:We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate

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“…Genes with cell type and/or state specific expression can hold particular functional relevance in the condition to which their expression is biased [ 28 ], and could be targeted by gene therapy approaches with minimal effects on neighbouring cells. Cell type-enriched lncRNAs could be less likely to be annotated in GENCODE than ubiquitously expressed lncRNAs.…”

Section: Resultsmentioning

confidence: 99%

Novel Transcript Discovery Expands the Repertoire of Pathologically-Associated, Long Non-Coding RNAs in Vascular Smooth Muscle Cells

Bennett

Ulitsky

Alloza

et al. 2021

IJMS

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Vascular smooth muscle cells (VSMCs) provide vital contractile force within blood vessel walls, yet can also propagate cardiovascular pathologies through proliferative and pro-inflammatory activities. Such phenotypes are driven, in part, by the diverse effects of long non-coding RNAs (lncRNAs) on gene expression. However, lncRNA characterisation in VSMCs in pathological states is hampered by incomplete lncRNA representation in reference annotation. We aimed to improve lncRNA representation in such contexts by assembling non-reference transcripts in RNA sequencing datasets describing VSMCs stimulated in vitro with cytokines, growth factors, or mechanical stress, as well as those isolated from atherosclerotic plaques. All transcripts were then subjected to a rigorous lncRNA prediction pipeline. We substantially improved coverage of lncRNAs responding to pro-mitogenic stimuli, with non-reference lncRNAs contributing 21–32% for each dataset. We also demonstrate non-reference lncRNAs were biased towards enriched expression within VSMCs, and transcription from enhancer sites, suggesting particular relevance to VSMC processes, and the regulation of neighbouring protein-coding genes. Both VSMC-enriched and enhancer-transcribed lncRNAs were large components of lncRNAs responding to pathological stimuli, yet without novel transcript discovery 33–46% of these lncRNAs would remain hidden. Our comprehensive VSMC lncRNA repertoire allows proper prioritisation of candidates for characterisation and exemplifies a strategy to broaden our knowledge of lncRNA across a range of disease states.

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A limited set of transcriptional programs define major cell types

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Cited by 30 publications

References 41 publications

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci

Novel Transcript Discovery Expands the Repertoire of Pathologically-Associated, Long Non-Coding RNAs in Vascular Smooth Muscle Cells

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