Dynamic regulation of pancreatic β cell function and gene expression by the SND1 coregulator in vitro

dc.contributor.authorKanojia, Sukrati
dc.contributor.authorDavidson, Rebecca K.
dc.contributor.authorConley, Jason M.
dc.contributor.authorXu, Jerry
dc.contributor.authorOsmulski, Meredith
dc.contributor.authorSims, Emily K.
dc.contributor.authorRen, Hongxia
dc.contributor.authorSpaeth, Jason M.
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicine
dc.date.accessioned2024-03-26T10:14:18Z
dc.date.available2024-03-26T10:14:18Z
dc.date.issued2023
dc.description.abstractThe pancreatic β cell synthesizes, packages, and secretes insulin in response to glucose-stimulation to maintain blood glucose homeostasis. Under diabetic conditions, a subset of β cells fail and lose expression of key transcription factors (TFs) required for insulin secretion. Among these TFs is Pancreatic and duodenal homeobox 1 (PDX1), which recruits a unique subset of transcriptional coregulators to modulate its activity. Here we describe a novel interacting partner of PDX1, the Staphylococcal Nuclease and Tudor domain-containing protein (SND1), which has been shown to facilitate protein-protein interactions and transcriptional control through diverse mechanisms in a variety of tissues. PDX1:SND1 interactions were confirmed in rodent β cell lines, mouse islets, and human islets. Utilizing CRISPR-Cas9 gene editing technology, we deleted Snd1 from the mouse β cell lines, which revealed numerous differentially expressed genes linked to insulin secretion and cell proliferation, including limited expression of Glp1r. We observed Snd1 deficient β cell lines had reduced cell expansion rates, GLP1R protein levels, and limited cAMP accumulation under stimulatory conditions, and further show that acute ablation of Snd1 impaired insulin secretion in rodent and human β cell lines. Lastly, we discovered that PDX1:SND1 interactions were profoundly reduced in human β cells from donors with type 2 diabetes (T2D). These observations suggest the PDX1:SND1 complex formation is critical for controlling a subset of genes important for β cell function and is targeted in diabetes pathogenesis.
dc.eprint.versionFinal published version
dc.identifier.citationKanojia S, Davidson RK, Conley JM, et al. Dynamic regulation of pancreatic β cell function and gene expression by the SND1 coregulator in vitro. Islets. 2023;15(1):2267725. doi:10.1080/19382014.2023.2267725
dc.identifier.urihttps://hdl.handle.net/1805/39509
dc.language.isoen_US
dc.publisherTaylor & Francis
dc.relation.isversionof10.1080/19382014.2023.2267725
dc.relation.journalIslets
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePMC
dc.subjectCoregulator
dc.subjectSND1
dc.subjectInsulin secretion
dc.subjectTranscription
dc.subjectTranscription factor
dc.subjectType 2 diabetes
dc.subjectβ cell
dc.titleDynamic regulation of pancreatic β cell function and gene expression by the SND1 coregulator in vitro
dc.typeArticle
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