SCGN deficiency results in colitis susceptibility

Sifuentes-Dominguez, Luis; Li, Haiying; Llano, Ernesto M.; Liu, Zhe; Singla, Anuj; Patel, Ashish; Kathania, Mahesh; Khoury, Areen; Norris, Nicholas; Rios, Jonathan J.; Starokadomskyy, Petro; Park, Jason; Gopal, Purva; Liu, Qi; Tan, Shuxin; Chan, Lillienne; Ross, Theodora S.; Harrison, Steven M.; Venuprasad, K.; Baker, Linda A.; Jia, Da; Burstein, Ezra

doi:10.7554/elife.49910

Cited by 21 publications

(21 citation statements)

References 60 publications

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“…Secretagogin, EF-hand calcium binding protein ( SCGN ) expresses in normal endocrine tissues, such as neuroendocrine cells of gastrointestinal tract [ 37 ]. In mice, Scgn gene deficient leads to colitis, which highlights the role of Scgn in intestinal immune homeostasis [ 38 ]. The expression of bestrophin 4 ( BEST4 ) is decreased in colon tumor, colon adenocarcinoma and rectal adenocarcinoma and CRC [ 39 – 42 ].…”

Section: Discussionmentioning

confidence: 99%

Uncovering potential genes in colorectal cancer based on integrated and DNA methylation analysis in the gene expression omnibus database

et al. 2022

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Background Colorectal cancer (CRC) is major cancer-related death. The aim of this study was to identify differentially expressed and differentially methylated genes, contributing to explore the molecular mechanism of CRC. Methods Firstly, the data of gene transcriptome and genome-wide DNA methylation expression were downloaded from the Gene Expression Omnibus database. Secondly, functional analysis of differentially expressed and differentially methylated genes was performed, followed by protein-protein interaction (PPI) analysis. Thirdly, the Cancer Genome Atlas (TCGA) dataset and in vitro experiment was used to validate the expression of selected differentially expressed and differentially methylated genes. Finally, diagnosis and prognosis analysis of selected differentially expressed and differentially methylated genes was performed. Results Up to 1958 differentially expressed (1025 up-regulated and 993 down-regulated) genes and 858 differentially methylated (800 hypermethylated and 58 hypomethylated) genes were identified. Interestingly, some genes, such as GFRA2 and MDFI, were differentially expressed-methylated genes. Purine metabolism (involved IMPDH1), cell adhesion molecules and PI3K-Akt signaling pathway were significantly enriched signaling pathways. GFRA2, FOXQ1, CDH3, CLDN1, SCGN, BEST4, CXCL12, CA7, SHMT2, TRIP13, MDFI and IMPDH1 had a diagnostic value for CRC. In addition, BEST4, SHMT2 and TRIP13 were significantly associated with patients’ survival. Conclusions The identified altered genes may be involved in tumorigenesis of CRC. In addition, BEST4, SHMT2 and TRIP13 may be considered as diagnosis and prognostic biomarkers for CRC patients.

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Section: Discussionmentioning

confidence: 99%

Uncovering potential genes in colorectal cancer based on integrated and DNA methylation analysis in the gene expression omnibus database

et al. 2022

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“…Both were supplemented with 10% FBS. SCGN and SNAP-25 deficient STC-1 cell lines and SCGN-deficient NIT-1 cell line were generated using lentiviral CRISPR/Cas9 system targeting exon 1, as previously reported (31,39). Transduced cells were puromycin-selected and clonally isolated using serial dilutions.…”

Section: Methodsmentioning

confidence: 99%

“…GLP-1 Secretion Assays. GLP-1secreation assays were performed as previously described (31). Briefly, DHA (Nu-chek, U-84-A) was dissolved in 100% ethanol at a concentration of 10 mg/mL, frozen with liquid N 2 , and stored at −20°C.…”

Section: Methodsmentioning

confidence: 99%

“…Emphasizing the importance of SCGN in human physiology is the observation that SCGN deficiency has been linked to the pathogenesis of multiple diseases, such as neurodegeneration, autism, and schizophrenia (19,(28)(29)(30). More recently, deficiency in SCGN was shown to contribute to inflammatory bowel disease (31). In contrast with the wealth of information regarding the cellular and physiological functions of SCGN, little is known about the mechanisms by which SCGN regulates exocytosis in diverse cellular events.…”

Section: Significancementioning

confidence: 99%

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Structural and mechanistic insights into secretagogin-mediated exocytosis

Qin

Liu

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Secretagogin (SCGN) is a hexa–EF-hand protein that is highly expressed in the pancreas, brain, and gastrointestinal tract. SCGN is known to modulate regulated exocytosis in multiple cell lines and tissues; however, its exact functions and underlying mechanisms remain unclear. Here, we report that SCGN interacts with the plasma membrane SNARE SNAP-25, but not the assembled SNARE complex, in a Ca2+-dependent manner. The crystal structure of SCGN in complex with a SNAP-25 fragment reveals that SNAP-25 adopts a helical structure and binds to EF-hands 5 and 6 of SCGN. SCGN strongly inhibits SNARE-mediated vesicle fusion in vitro by binding to SNAP-25. SCGN promotes the plasma membrane localization of SNAP-25, but not Syntaxin-1a, in SCGN-expressing cells. Finally, SCGN controls neuronal growth and brain development in zebrafish, likely via interacting with SNAP-25 or its close homolog, SNAP-23. Our results thus provide insights into the regulation of SNAREs and suggest that aberrant synapse functions underlie multiple neurological disorders caused by SCGN deficiency.

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“…Microbial DNA was purified using a QIAamp Mini Column (QIAGEN). For stool content, fresh fecal pellets and ileal liquid content obtained during intestinal dissection were immediately frozen in liquid nitrogen and stored until use, according to standard protocols ( Sifuentes-Dominguez et al, 2019 ). DNA was extracted using QIAGEN power fecal kit according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Paneth cell–derived growth factors support tumorigenesis in the small intestine

et al. 2020

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Paneth cells (PCs) are small intestinal epithelial cells that secrete antimicrobial peptides and growth factors, such as Wnt ligands. Intriguingly, the context in which PC-derived Wnt secretion is relevant in vivo remains unknown as intestinal epithelial ablation of Wnt does not affect homeostatic proliferation or restitution after irradiation injury. Considering the importance of growth factors in tumor development, we explored here the role of PCs in intestinal carcinogenesis using a genetic model of PC depletion through conditional expression of diphtheria toxin-α subunit. PC depletion in ApcMin mice impaired adenoma development in the small intestine and led to decreased Wnt3 expression in small bowel adenomas. To determine if PC-derived Wnt3 was required for adenoma development, we examined tumor formation after PC-specific ablation of Wnt3. We found that this was sufficient to decrease small intestinal adenoma formation; moreover, organoids derived from these tumors displayed slower growth capacity. Overall, we report that PC-derived Wnt3 is required to sustain early tumorigenesis in the small bowel and identify a clear role for PC-derived Wnt production in intestinal pathology.

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SCGN deficiency results in colitis susceptibility

Cited by 21 publications

References 60 publications

Uncovering potential genes in colorectal cancer based on integrated and DNA methylation analysis in the gene expression omnibus database

Uncovering potential genes in colorectal cancer based on integrated and DNA methylation analysis in the gene expression omnibus database

Structural and mechanistic insights into secretagogin-mediated exocytosis

Paneth cell–derived growth factors support tumorigenesis in the small intestine

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