SOX4 Allows Facultative β-Cell Proliferation Through Repression of <i>Cdkn1a</i>

Xu, Eric E.; Sasaki, Shugo; Speckmann, Thilo; Nian, Cuilan; Lynn, Francis C.

doi:10.2337/db16-1074

Cited by 21 publications

(26 citation statements)

References 36 publications

(33 reference statements)

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“…4; Additional file 9: Figure S8) as candidate functional genes, including SOX4 ([PCS = 0.62] at the locus usually named for CDKAL1 ) and ATXN7 ([PCS = 0.57] at the locus named for ADAMTS9 ). In the former case, our prioritisation of SOX4 has been validated by subsequent experimental studies which have demonstrated a direct relationship between perturbation of SOX4 and insulin secretion and beta-cell proliferation ([50, 51]).…”

Section: Resultsmentioning

confidence: 67%

Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data

et al. 2019

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Background Genome-wide association studies (GWAS) have identified several hundred susceptibility loci for type 2 diabetes (T2D). One critical, but unresolved, issue concerns the extent to which the mechanisms through which these diverse signals influencing T2D predisposition converge on a limited set of biological processes. However, the causal variants identified by GWAS mostly fall into a non-coding sequence, complicating the task of defining the effector transcripts through which they operate. Methods Here, we describe implementation of an analytical pipeline to address this question. First, we integrate multiple sources of genetic, genomic and biological data to assign positional candidacy scores to the genes that map to T2D GWAS signals. Second, we introduce genes with high scores as seeds within a network optimization algorithm (the asymmetric prize-collecting Steiner tree approach) which uses external, experimentally confirmed protein-protein interaction (PPI) data to generate high-confidence sub-networks. Third, we use GWAS data to test the T2D association enrichment of the “non-seed” proteins introduced into the network, as a measure of the overall functional connectivity of the network. Results We find (a) non-seed proteins in the T2D protein-interaction network so generated (comprising 705 nodes) are enriched for association to T2D ( p = 0.0014) but not control traits, (b) stronger T2D-enrichment for islets than other tissues when we use RNA expression data to generate tissue-specific PPI networks and (c) enhanced enrichment ( p = 3.9 × 10 − 5 ) when we combine the analysis of the islet-specific PPI network with a focus on the subset of T2D GWAS loci which act through defective insulin secretion. Conclusions These analyses reveal a pattern of non-random functional connectivity between candidate causal genes at T2D GWAS loci and highlight the products of genes including YWHAG , SMAD4 or CDK2 as potential contributors to T2D-relevant islet dysfunction. The approach we describe can be applied to other complex genetic and genomic datasets, facilitating integration of diverse data types into disease-associated networks. Electronic supplementary material The online version of this article (10.1186/s13073-019-0628-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 67%

Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data

et al. 2019

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“…Moreover, recent studies found that Sox4 has a role in insulin secretion in adult b-cells and that mutations in the Sox4 gene are associated with an increased risk of developing type 2 diabetes (22)(23)(24). Mechanistic studies further showed that Sox4 allows b-cell proliferation and replication through direct repression of p21 CIP1 (25). In addition, expression of Sox4 was also shown to participate in skeletal muscle differentiation (26).…”

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confidence: 99%

SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c

et al. 2018

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Obesity is usually associated with an increased risk of nonalcoholic fatty liver disease that is characterized by accumulation of excessive triglyceride (TG) in hepatocytes. However, the factors involved in the obesity-induced hepatosteatosis are poorly defined. Here, we report that SRY-box containing gene 4 (), a transcription factor that regulates cell proliferation and differentiation, plays an important role in hepatic TG metabolism. expression levels are markedly upregulated in livers of obese rodents and humans. Adenovirus-medicated overexpression of in the livers of lean mice promotes liver steatosis, whereas liver-specific knockdown of ameliorates TG accumulation and improves insulin resistance in obese mice. At the molecular level, we show that could directly control the transcription of gene through binding to its proximal promoter region. Thus, we have identified as an important component of hepatic TG metabolism.

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“…SOX4 is an important member of the SOX transcription factor family, and interference with its expression inhibits tumor cell proliferation and promotes apoptosis. 23 SOX4 plays a critical role in the development of colorectal cancer. The high expression of SOX4 can inhibit the proliferation and invasion of colorectal cancer cells.…”

Section: Introductionmentioning

confidence: 99%

<p>Upregulation of FTX Promotes Osteosarcoma Tumorigenesis by Increasing SOX4 Expression via miR-214-5p</p>

Chen¹,

Liu²,

Ouyang³

et al. 2020

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Background Long-chain non-coding RNA (LncRNA) plays a key role in the biological processes of tumors. LncRNA-FTX has been the invasion of tumors. However, its function and mechanism in osteosarcoma have not been studied. Methods qRT-PCR was measured the expression levels of FTX and miR-214-5p in osteosarcoma. The protein levels of SRY-related HMG box transcription factor 4 (SOX4) were detected by Western Blot. Cholecystokinin (CCK-8) assay, cell colony formation and Transwell assay, Annexin V-FITC/PI assay were analyzed the effects of FTX and miR-214-5p on cell proliferation, cell invasion and apoptosis. The relationship between FTX, miR-214-5p and SOX4 was analyzed by bioinformatics analysis and Luciferase. The tumor changes in mice were detected by vivo experiments in nude mice. Results The expression levels of FTX were increased in osteosarcoma tissues and cell lines and negatively correlated with the expression levels of miR-214-5p. FTX could modulate the expression of miR-214-5p in osteosarcoma cell lines. sh-FTX inhibited the growth and metastasis of osteosarcoma. FTX could regulate the growth of osteosarcoma through miR-214-5p. The knockdown of miR-214-5p reversed the inhibitory effect of sh-FTX on osteosarcoma cell proliferation and growth in mice. Furthermore, FTX regulated the expression of SOX4 by acting as a sponge of miR-214-5p in osteosarcoma. Conclusion FTX could promote proliferation, invasion and inhibited apoptosis by regulating miR-214-5p/SOX4 axis in osteosarcoma, suggesting that FTX might be a potential target for osteosarcoma treatment.

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SOX4 Allows Facultative β-Cell Proliferation Through Repression of Cdkn1a

Cited by 21 publications

References 36 publications

Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data

Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data

SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c

<p>Upregulation of FTX Promotes Osteosarcoma Tumorigenesis by Increasing SOX4 Expression via miR-214-5p</p>

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