Adaptation to chronic ER stress enforces pancreatic beta-cell plasticity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA731067 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14585400.fastq.gz | Fastqsanger.gz | |||
| SRR14585401.fastq.gz | Fastqsanger.gz | |||
| SRR14585402.fastq.gz | Fastqsanger.gz | |||
| SRR14585403.fastq.gz | Fastqsanger.gz | |||
| SRR14585404.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise β-cell identity is unknown. We show here under reversible, chronic stress conditions β-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of β-cell function and identity. Upon recovery from stress, β-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while β-cells show resilience to episodic ER stress, when episodes exceed a threshold, β-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest β-cell adaptive exhaustion contributes to diabetes pathogenesis.
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Project description:Phenotypic plasticity and local adaptation via genetic change are two major mechanisms of response to dynamic environmental conditions. These mechanisms are not mutually exclusive, since genetic change can establish similar phenotypes to plasticity. This connection between both mechanisms raises the question of how much of the variation observed between species or populations is plastic and how much of it is genetic. In this study, we used a structured population of fire salamanders (Salamandra salamandra), in which two subpopulations differ in terms of physiology, genetics, mate-, and habitat preferences. Our goal was to identify candidate genes for differential habitat adaptation in this system, and to explore the degree of plasticity compared to local adaptation. We therefore performed a reciprocal transfer experiment of stream- and pond-originated salamander larvae and analyzed changes in morphology and transcriptomic profile (using species-specific microarrays). We observed that stream- and pond-originated individuals diverge in morphology and gene expression. For instance, pond-originated larvae have larger gills, likely to cope with oxygen-poor ponds. When transferred to streams, pond-originated larvae showed a high degree of plasticity, resembling the morphology and gene expression of stream-originated larvae (reversion); however the same was not found for stream-originated larvae when transferred to ponds, where the expression of genes related to reduction-oxidation processes was increased, possibly to cope with environmental stress. The lack of symmetrical responses between transplanted animals highlights the fact that the adaptations are not fully plastic and that some level of local adaptation has already occurred in this population. This study illuminates the process by which phenotypic plasticity allows local adaptation to new environments and its potential role in the pathway of incipient speciation.
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Project description:The large secretory glycoprotein, thyroglobulin, is the primary translation product of thyroid follicular cells. This difficult-to-fold protein is readily susceptible to structural alterations that render the misfolded thyroglobulin unable to be exported from the endoplasmic reticulum (ER) a known cause of congenital hypothyroidism, with severe, chronic thyrocyte ER stress. Nevertheless, patients with this disease commonly grow a goiter indicative of thyroid cell survival and adaptation. To model this, we have treated PCCl3 thyrocytes with continuous exposure to tunicamcyin (causing an ER stress that can be specifically attributed to thyroglobulin misfolding). In response, PCCl3 cells escape by downregulating expression of Mfsd2a (the tunicamycin transporter). By contrast, following CRISPR/Cas9-mediated deletion of Mfsd2a, PCCl3 cells cannot escape the continuous, chronic effects of high-dose tunicamycin (as demonstrated by persistent accumulation of unglycosylated thyroglobulin); nevertheless the thyrocytes live and grow. A comprehensive proteomic analysis of these cells adapted to chronic ER protein misfolding reveals many hundreds of up-regulated proteins, supporting stimulation of ER chaperones, oxidoreductases, and stress responses as well as lipid biosynthesis pathways. Further, we noted: a) increased phospho-AMP-kinase-B (suggesting upregulated AMPK activity) and decreased phospho-S6 and protein translation (suggesting decreased mTOR activity), consistent with conserved cell survival/adaptation pathways; and b) a suggestion of less differentiated thyrocyte phenotype with decreased PAX8, FOXE1, and TPO protein, as well as a significant decrease of thyroglobulin mRNA levels.
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