Transcriptomic identification of TMIGD1 and its relationship with the ileal epithelial cell differentiation in Crohn’s disease

Zabana, Yamile; Lorén, Violeta; Domènech, Eugeni; Aterido, Adrià; Garcia-Jaraquemada, Arce; Juliá, Antonio; Vicario, María; Pedrosa, E.; Ferreiro, M. J.; Troya, José M.; Lozano, Juan José; Sarrias, María Rosa; Cabré, Eduard; Mañosa, Míriam; Manyé, Josep

doi:10.1152/ajpgi.00027.2020

Cited by 16 publications

(25 citation statements)

References 55 publications

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“…Remarkably, we also found NECAB3 among the top-scoring genes: This calcium binding protein inhibits the association of X11L with amyloid precursor protein and abolishes the suppression of beta-amyloid production by X11L [25,26]. We could not find any reliable reference describing an association between TMIGD1 and Alzheimer's disease, but it was associated with Crohn's disease [27], and in turn inflammatory bowel disease seems to be related to Alzheimer's [28].…”

Section: Genotype-level Twasmentioning

confidence: 64%

Prediction of gene expression from regulatory sequence composition enhances transcriptome-wide association studies

Marotta

Mozafari

Grassi

et al. 2021

Preprint

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Transcriptome-wide association studies (TWAS) can prioritize trait-associated genes by finding correlations between a trait and the genetically regulated component of gene expression. A basic ingredient of a TWAS is a regression model, typically trained in an external reference data set, used to impute the genetically-regulated expression. We devised a model that improves the accuracy of the imputation by using, as predictors, not the genotypes directly but rather the sequence composition of the proximal gene regulatory region, expressed as its profile of affinities for a set of position weight matrices. When trained on 48 tissues from GTEx, the regression model showed improved performance compared with models regressing expression directly on the genotype. We imputed the expression levels in genotyped individuals from the ADNI data set, and used the imputed expression to perform a TWAS. We also developed a method to perform the TWAS based on summary statistics from genome-wide association studies, and applied it to 11 complex traits from the UK Biobank. The greater accuracy in the prediction of gene expression allowed us to report hundreds of new gene-phenotype association candidates.

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Section: Genotype-level Twasmentioning

confidence: 64%

Prediction of gene expression from regulatory sequence composition enhances transcriptome-wide association studies

Marotta

Mozafari

Grassi

et al. 2021

Preprint

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“…TMIGD1 is predominantly expressed by epithelial cells of the kidney (Arafa et al , 2015; Hartmann et al , 2020) and of the small intestine (Cattaneo et al , 2011; Zabana et al , 2020). In two colon-derived cell lines, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Both ezrin and EBP50 play critical roles in microvilli formation and dynamics (Garbett & Bretscher, 2012; Garbett et al ., 2010; LaLonde et al ., 2010; Viswanatha et al ., 2012). Recent studies described TMIGD1 as component of the apical membrane of enterocytes whose absence results in a defective BB membrane (De La Cena et al , 2020; Zabana et al ., 2020). Our findings thus identify TMIGD1 as part of an adhesive complex at the micorvillar base and describe a mechanism though which TMIGD1 regulates microvilli formation.…”

Section: Discussionmentioning

confidence: 99%

“…TMIGD1 has been described to be predominantly expressed by epithelial cells of the kidney and of the intestine (Arafa et al ., 2015; Cattaneo et al ., 2011; Meyer et al , 2018). Its expression is downregulated during malignant transformation and during inflammation both in the kidney (Arafa et al ., 2015; Meyer et al ., 2018) and in the intestine (Cattaneo et al ., 2011; Lee et al , 2015; Mojica & Hawthorn, 2010; Roberts et al , 2015; Zabana et al ., 2020) suggesting a tumor-suppressive function. The reduction and/or loss of TMIGD1 expression during cellular transformation might explain the low expression levels of TMIGD1 in many cell lines derived from kidney or intestine (Cattaneo et al ., 2011; Meyer et al ., 2018) and might also be responsible for our observation of TMIGD1 expression in only a fraction of colon carcinoma-derived Caco-2 and T84 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

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A novel adhesive complex at the base of intestinal microvilli

Hartmann

Thuering

Michels³

et al. 2021

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Intestinal epithelial cells form dense arrays of microvilli at the apical membrane to enhance their functional capacity. Microvilli contain a protocadherin-based intermicrovillar adhesion complex localized at their tips which regulates microvillar length and packaging. Here, we identify a second adhesive complex in microvilli of intestinal epithelial cells. This complex is localized at the basal region of microvilli and consists of the adhesion molecule TMIGD1, the phosphoprotein EBP50 and the F-actin – plasma membrane cross-linking protein ezrin. Ternary complex formation requires unmasking of the EBP50 PDZ domains by ezrin binding and is strongly enhanced upon mutating Ser162 located in PDZ domain 2 of EBP50. Dephosphorylation of EBP50 at S162 is mediated by PP1α, a serine/threonine phosphatase localized at the microvillar base and involved in ezrin phosphocycling. Importantly, the binding of EBP50 to TMIGD1 enhances the dynamic turnover of EBP50 at microvilli in a Ser162 phosphorylation-dependent manner. We identify an adhesive complex at the microvillar base and propose a potential mechanism that regulates microvillar dynamics in enterocytes.

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“…TMIGD1 is not a very well-studied gene; however, it is known to be speci cally expressed in intestinal tissue and epithelial cells [53]. TMIGD1 is a glycoprotein located on the cell surface and consists of one or several immunoglobulins, a single transmembrane domain and an intracellular C-terminus.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-derived microRNA-223 Promotes Intestinal Mucosal Barrier Dysfunction via Exosomal Pathways in Inflammatory Bowel Disease

Chang¹,

Song

et al. 2021

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Background & Aim: Exosomes are effective mediators of cell-to-cell interactions and carry many regulatory molecules, including miRNAs, that can play crucial roles in diverse fundamental biological processes. However, to date, no study has reported macrophage exosomal involvement in the development of inflammatory bowel disease (IBD). This study investigated the specific miRNAs in macrophage-derived exosomes in IBD and the potential molecular mechanism. Methods: Dextran sulfate sodium (DSS) was used to generate IBD mice. The supernatants of murine bone marrow-derived macrophages (BMDMs) with or without lipopolysaccharide (LPS) were collected for exome isolation and miRNA sequencing. Lentiviruses were used to modify miRNA expression and further investigate the role of macrophage-derived exosomal miRNAs. In vitro, both mouse and human organoids were applied to a Transwell system in co-culture with BMDMs as a cellular IBD-related challenge.Results: Here, we show that LPS-induced macrophages can release exosomes containing various miRNAs, aggravating IBD. We analyzed miRNA sequencing of macrophage-derived exosomes, and miR-223 was selected for further study. In vivo, exosomes with high miR-223 expression contributed to the exacerbation of intestinal barrier dysfunction, which was further verified in both mouse and human colon organoids. Furthermore, time-dependent analysis of the mRNAs of DSS-induced colitis mouse tissue combined with miR-223 target gene prediction was performed to select the candidate gene, and the barrier-related factor TMIGD1 was identified.Conclusion: Collectively, these data indicated that macrophage-derived exosomal miR-223 played a novel role in intestinal barrier dysfunction by inhibiting TMIGD1 in the progression of DSS-induced colitis.

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Transcriptomic identification of TMIGD1 and its relationship with the ileal epithelial cell differentiation in Crohn’s disease

Cited by 16 publications

References 55 publications

Prediction of gene expression from regulatory sequence composition enhances transcriptome-wide association studies

Prediction of gene expression from regulatory sequence composition enhances transcriptome-wide association studies

A novel adhesive complex at the base of intestinal microvilli

Macrophage-derived microRNA-223 Promotes Intestinal Mucosal Barrier Dysfunction via Exosomal Pathways in Inflammatory Bowel Disease

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