Transcriptional analysis of islets of Langerhans from organ donors of different ages

Seiron, Peter; Stenwall, Anton; Hedin, A.; Granlund, Louise; Esguerra, Jonathan L.S.; Volkov, Petr; Renström, Erik; Korsgren, Olle; Lundberg, Marcus; Skog, Oskar

doi:10.1371/journal.pone.0247888

Cited by 15 publications

(18 citation statements)

References 47 publications

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“…Furthermore, genes involved in endoplasmic reticulum (ER) stress and unfolded protein response (UPR) ( XBP1, DDIT3, EDEM1, ERN1, ATF4, ATF6, HSPA5, HSP90B1 ), which are involved in beta cell adaptive and terminal UPR, were not significantly changed between control and bleomycin treatment ( Supplementary Figure 6 ). Comparison of the list of differentially expressed genes in our dataset with recently generated human islet RNA-seq datasets during aging [44] and adult human islets treated with the cytokine IFNα [45] showed that there were only 74/385 (∼19%) age-related genes in common and only 256/1894 (∼13%) IFNα-regulated genes in common, respectively, ( Supplementary Figure 7A and 7B, Supplementary Table 1 ). This suggested that the transcriptional response during islet DDR activation and senescence is generally different from natural aging and cytokine exposure.…”

Section: Resultsmentioning

confidence: 96%

“…Using an unbiased analysis by RNA-seq, we found that DDR activation and senescence induction by bleomycin treatment of islets resulted in a coordinated p53-p21 transcriptional program, involving downregulation of genes involved in proliferation and cell cycle progression and upregulation of p53-targeted genes. Although there were a small subset of genes in common with other human islet RNA-seq datasets representing natural aging [48] or cytokine exposure [53] the changes during islet DDR activation and senescence were largely distinct. Importantly, the changes in this model occur 4 days after drug removal (6 days post-treatment) and thus reflect a stable phenotypic change rather than an acute response.…”

Section: Discussionmentioning

confidence: 99%

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DNA damage models phenotypes of β cell senescence in Type 1 Diabetes

Brawerman

Thompson

2021

Preprint

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Pancreatic beta cells are essential endocrine cells in the islets of Langerhans that respond to increases in blood glucose by secreting insulin and their dysfunction and death drives the development of diabetes. Beta cell senescence involving a DNA damage response (DDR) was recently shown to contribute to the pathogenesis of Type 1 Diabetes (T1D), however, a basic mechanistic understanding of how senescence develops in beta cells is lacking. Here, we investigated senescent phenotypes arising in the mouse beta cell line NIT1 derived from the T1D susceptible nonobese diabetic (NOD) mouse strain and the transcriptome response in human islets after induction of DNA damage. Sub-lethal DNA damage in NIT1 cells led to several classical hallmarks of senescence including the DDR, growth arrest, enlarged flattened morphology and a senescence-associated secretory phenotype (SASP) resembling what occurs during T1D. RNA-seq analysis on human islets with DNA double-strand break damage revealed a coordinated p53-p21 transcriptional response and upregulation of genes involved in prosurvival signaling and SASP. Taken together, these findings suggest that some of the phenotypes of mouse and human beta cell senescence during T1D can be induced by DNA damage in NIT1 cells and human islets in culture.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

DNA damage models phenotypes of β cell senescence in Type 1 Diabetes

Brawerman

Thompson

2021

Preprint

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“…It is therefore possible that ZBED6, by enhancing expression of this and other growth-controlling genes, maintains normal beta cell replication, ensuring an adequate beta cell mass for the long-term preservation of glucose tolerance. Interestingly, ZBED6 expression appears to be reduced in human beta cells with increasing age [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

ZBED6 counteracts high-fat diet-induced glucose intolerance by maintaining beta cell area and reducing excess mitochondrial activation

et al. 2021

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Aims/hypothesis ZBED6 (zinc finger, BED-type containing 6) is known to regulate muscle mass by suppression of Igf2 gene transcription. In insulin-producing cell lines, ZBED6 maintains proliferative capacity at the expense of differentiation and beta cell function. The aim was to study the impact of Zbed6 knockout on beta cell function and glucose tolerance in C57BL/6 mice. Methods Beta cell area and proliferation were determined in Zbed6 knockout mice using immunohistochemical analysis. Muscle and fat distribution were assessed using micro-computed tomography. Islet gene expression was assessed by RNA sequencing. Effects of a high-fat diet were analysed by glucose tolerance and insulin tolerance tests. ZBED6 was overexpressed in EndoC-βH1 cells and human islet cells using an adenoviral vector. Beta cell cell-cycle analysis, insulin release and mitochondrial function were studied in vitro using propidium iodide staining and flow cytometry, ELISA, the Seahorse technique, and the fluorescent probes JC-1 and MitoSox. Results Islets from Zbed6 knockout mice showed lowered expression of the cell cycle gene Pttg1, decreased beta cell proliferation and decreased beta cell area, which occurred independently from ZBED6 effects on Igf2 gene expression. Zbed6 knockout mice, but not wild-type mice, developed glucose intolerance when given a high-fat diet. The high-fat diet Zbed6 knockout islets displayed upregulated expression of oxidative phosphorylation genes and genes associated with beta cell differentiation. In vitro, ZBED6 overexpression resulted in increased EndoC-βH1 cell proliferation and a reduced glucose-stimulated insulin release in human islets. ZBED6 also reduced mitochondrial JC-1 J-aggregate formation, mitochondrial oxygen consumption rates (OCR) and mitochondrial reactive oxygen species (ROS) production, both at basal and palmitate + high glucose-stimulated conditions. ZBED6-induced inhibition of OCR was not rescued by IGF2 addition. ZBED6 reduced levels of the mitochondrial regulator PPAR-γ related coactivator 1 protein (PRC) and bound its promoter/enhancer region. Knockdown of PRC resulted in a lowered OCR. Conclusions/interpretation It is concluded that ZBED6 is required for normal beta cell replication and also limits excessive beta cell mitochondrial activation in response to an increased functional demand. ZBED6 may act, at least in part, by restricting PRC-mediated mitochondrial activation/ROS production, which may lead to protection against beta cell dysfunction and glucose intolerance in vivo. Graphical abstract

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“…Expression profiling by high throughput sequencing dataset GSE162689 [25] was obtained from GEO database. The dataset comprised total 59 samples, of which 27 were from T1DM samples and 32 were from normal control samples and was based on the GPL24014 Ion Torrent S5 XL (Homo sapiens).…”

Section: Methodsmentioning

confidence: 99%

“…We downloaded expression profiling by high throughput sequencing dataset GSE162689 [25], from Gene Expression Omnibus database (GEO) (http://www.ncbi.nlm.nih.gov/geo/) [26], which contain gene expression data from T1DM samples and normal control samples. We then performed deep bioinformatics analysis, including identifying common differential expressed genes (DEGs), gene ontology (GO) enrichment analysis, REACTOME pathway enrichment analysis, and construction and analysis of protein-protein interaction (PPI) network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network.…”

Section: Introductionmentioning

confidence: 99%

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

Bm¹,

Cm²

2021

Preprint

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Type 1 diabetes mellitus (T1DM) is a metabolic disorder for which the underlying molecular mechanisms remain largely unclear. This investigation aimed to elucidate essential candidate genes and pathways in T1DM by integrated bioinformatics analysis. In this study, differentially expressed genes (DEGs) were analyzed using DESeq2 of R package from GSE162689 of the Gene Expression Omnibus (GEO). Gene ontology (GO) enrichment analysis, REACTOME pathway enrichment analysis, and construction and analysis of protein-protein interaction (PPI) network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network, and validation of hub genes were then performed. A total of 952 DEGs (477 up regulated and 475 down regulated genes) were identified in T1DM. GO and REACTOME enrichment result results showed that DEGs mainly enriched in multicellular organism development, detection of stimulus, diseases of signal transduction by growth factor receptors and second messengers, and olfactory signaling pathway. The top hub genes such as MYC, EGFR, LNX1, YBX1, HSP90AA1, ESR1, FN1, TK1, ANLN and SMAD9 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Receiver operating characteristic curve (ROC) analysis and RT-PCR confirmed that these genes were significantly associated with T1DM. In conclusion, the identified DEGs, particularly the hub genes, strengthen the understanding of the advancement and progression of T1DM, and certain genes might be used as candidate target molecules to diagnose, monitor and treat T1DM.

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Transcriptional analysis of islets of Langerhans from organ donors of different ages

Cited by 15 publications

References 47 publications

DNA damage models phenotypes of β cell senescence in Type 1 Diabetes

DNA damage models phenotypes of β cell senescence in Type 1 Diabetes

ZBED6 counteracts high-fat diet-induced glucose intolerance by maintaining beta cell area and reducing excess mitochondrial activation

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

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