Home Type 2Single-cell perturbations decipher ribosomal stress-surveillance regulators in type 2 diabetes

Single-cell perturbations decipher ribosomal stress-surveillance regulators in type 2 diabetes

by Xianglong He
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Suzuki, K. et al. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature 627, 347–357 (2024).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Mahajan, A. et al. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nat. Genet. 50, 559–571 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Flannick, J. et al. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature 570, 71–76 (2019).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Suzuki, K. et al. Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population. Nat. Genet. 51, 379–386 (2019).

Article 
CAS 
PubMed 

Google Scholar 

Huyghe, J. R. et al. Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat. Genet. 45, 197–201 (2013).

Article 
CAS 
PubMed 

Google Scholar 

DiCorpo, D. et al. Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. Commun. Biol. 5, 756 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Cao, Y. et al. The ChinaMAP analytics of deep whole genome sequences in 10,588 individuals. Cell Res. 30, 717–731 (2020).

Article 
PubMed 
PubMed Central 

Google Scholar 

Walker, J. T. et al. Genetic risk converges on regulatory networks mediating early type 2 diabetes. Nature 624, 621–629 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Rottner, A. K. et al. A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk. Nat. Genet. 55, 54–65 (2023).

Article 
CAS 
PubMed 

Google Scholar 

Xue, D. et al. Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived beta-like cells. Cell Metab. 35, 1897–1914.e11 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Morris, J. A. et al. Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens. Science 380, eadh7699 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Schmidt, R. et al. CRISPR activation and interference screens decode stimulation responses in primary human T cells. Science 375, eabj4008 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Zhou, P. et al. Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer. Nature 624, 154–163 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Joazeiro, C. A. P. Mechanisms and functions of ribosome-associated protein quality control. Nat. Rev. Mol. Cell Biol. 20, 368–383 (2019).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Stein, K. C. et al. Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis. Nature 601, 637–642 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Costa-Mattioli, M. et al. The integrated stress response: from mechanism to disease. Science 368, eaat5314 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Snieckute, G. et al. ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging. Science 382, eadf3208 (2023).

Article 
CAS 
PubMed 

Google Scholar 

Vind, A. C. et al. Ribosomal stress-surveillance: three pathways is a magic number. Nucleic Acids Res. 48, 10648–10661 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Yan, L. L. et al. Ribosome quality control antagonizes the activation of the integrated stress response on colliding ribosomes. Mol. Cell 81, 614–628.e4 (2021).

Article 
CAS 
PubMed 

Google Scholar 

Cnop, M. et al. Endoplasmic reticulum stress and eIF2α phosphorylation: the Achilles heel of pancreatic β cells. Mol. Metab. 6, 1024–1039 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Cheng, Y. et al. Generation and characterization of transgenic mice expressing mouse Ins1 promoter for pancreatic β-cell-specific gene overexpression and knockout. Endocrinology 156, 2724–2731 (2015).

CAS 
PubMed 

Google Scholar 

Song, D. et al. YY1 deficiency in β-cells leads to mitochondrial dysfunction and diabetes in mice. Metabolism 112, 154353 (2020).

Article 
CAS 
PubMed 

Google Scholar 

Rubio-Navarro, A. et al. A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes. Nat. Cell Biol. 25, 565–578 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Kim-Muller, J. Y. et al. Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice. Nat. Commun. 7, 12631 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Lee, K. et al. XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and protects against diabetic beta cell failure during metabolic stress in mice. Diabetologia 65, 984–996 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Xin, Y. et al. Pseudotime ordering of single human β-cells reveals states of insulin production and unfolded protein response. Diabetes 67, 1783–1794 (2018).

Article 
CAS 
PubMed 

Google Scholar 

Eizirik, D. L. et al. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat. Rev. Endocrinol. 16, 349–362 (2020).

Article 
CAS 
PubMed 

Google Scholar 

Wang, J., et al. Isolation of mouse pancreatic islet Procr+ progenitors and long-term expansion of islet organoids in vitro. Nat. Protoc. 17, 1359–1384 (2022).

Article 
CAS 
PubMed 

Google Scholar 

Juszkiewicz, S. et al. Ribosome collisions trigger cis-acting feedback inhibition of translation initiation. Elife 9, e60038 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Sinha, N. K. et al. EDF1 coordinates cellular responses to ribosome collisions. Elife 9, e58828 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Prentzell et al. G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell 184, 655–674.e27 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Bley, N. et al. Stress granules are dispensable for mRNA stabilization during cellular stress. Nucleic Acids Res. 43, e26 (2015).

Article 
PubMed 

Google Scholar 

Yong, J. et al. Chop/Ddit3 depletion in β cells alleviates ER stress and corrects hepatic steatosis in mice. Sci. Transl. Med. 13, eaba9796 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Fu, S. et al. Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity. Sci. Transl. Med. 7, 292ra98 (2015).

Article 
PubMed 
PubMed Central 

Google Scholar 

Tang, X. et al. SARS-CoV-2 infection induces beta cell transdifferentiation. Cell Metab. 33, 1577–1591.e7 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Hickey, K. L. et al. GIGYF2 and 4EHP inhibit translation initiation of defective messenger RNAs to assist ribosome-associated quality control. Mol. Cell 79, 950–962.e6 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Juszkiewicz, S. et al. ZNF598 is a quality control sensor of collided ribosomes. Mol. Cell 72, 469–481.e7 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Oltion, K. et al. An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes. Cell 186, 346–362.e17 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Vujkovic, M. et al. Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nat. Genet. 52, 680–691 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Sakaue, S. et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat. Genet. 53, 1415–1424 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Xue, A. et al. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat. Commun. 9, 2941 (2018).

Article 
PubMed 
PubMed Central 

Google Scholar 

Yu, Y. et al. ZZEF1 is a histone reader and transcriptional coregulator of Krüppel-like factors. J. Mol. Biol. 433, 166722 (2021).

Article 
CAS 
PubMed 

Google Scholar 

Simms, C. L. et al. Ribosome collision is critical for quality control during no-go decay. Mol. Cell 68, 361–373.e5 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Yip, M. C. J. et al. Detecting and rescuing stalled ribosomes. Trends Biochem. Sci. 46, 731–743 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Shao, S. et al. Structure and assembly pathway of the ribosome quality control complex. Mol. Cell 57, 433–444 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Kostova, K. K. et al. CAT-tailing as a fail-safe mechanism for efficient degradation of stalled nascent polypeptides. Science 357, 414–417 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Wu, C. C. et al. Ribosome collisions trigger general stress responses to regulate cell fate. Cell 182, 404–416.e14 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Vind, A. C. et al. ZAKalpha recognizes stalled ribosomes through partially redundant sensor domains. Mol. Cell 78, 700–713.e7 (2020).

Article 
CAS 
PubMed 

Google Scholar 

Delepine, M. et al. EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat. Genet. 25, 406–409 (2000).

Article 
CAS 
PubMed 

Google Scholar 

Kanno, A. et al. GCN2 regulates pancreatic beta cell mass by sensing intracellular amino acid levels. JCI Insight 5, e128820 (2020).

Article 
PubMed 
PubMed Central 

Google Scholar 

Konermann, S. et al. Genome-scale transcriptional activation by an engineered CRISPR–Cas9 complex. Nature 517, 583–588 (2015).

Article 
CAS 
PubMed 

Google Scholar 

Dror, E. et al. Epigenetic dosage identifies two major and functionally distinct β cell subtypes. Cell Metab. 35, 821–836.e7 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).

Article 
PubMed 
PubMed Central 

Google Scholar 

Langmead, B. et al. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Li, B. et al. RSEM: accurate transcript quantification from RNA-seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Love, M. I. et al. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

Article 
PubMed 
PubMed Central 

Google Scholar 

Yu, G. et al. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287 (2012).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Hanzelmann, S. et al. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14, 7 (2013).

Article 
PubMed 
PubMed Central 

Google Scholar 

Qiu, X. et al. Reversed graph embedding resolves complex single-cell trajectories. Nat. Methods 14, 979–982 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Kramer, A. et al. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 30, 523–530 (2014).

Article 
PubMed 

Google Scholar 

Van de Sande, B. et al. A scalable SCENIC workflow for single-cell gene regulatory network analysis. Nat. Protoc. 15, 2247–2276 (2020).

Article 
PubMed 

Google Scholar 

Carlson, M. hgu133plus2.db: Affymetrix Human Genome U133 plus 2.0 array annotation data (chip hgu133plus2). R package v.3. Bioconductor https://bioconductor.org/packages/release/data/annotation/html/hgu133plus2.db.html (2016).

Horlbeck, M. A. et al. Compact and highly active next-generation libraries for CRISPR-mediated gene repression and activation. Elife 5, e19760 (2016).

Article 
PubMed 
PubMed Central 

Google Scholar 

Replogle, J. M. et al. Combinatorial single-cell CRISPR screens by direct guide RNA capture and targeted sequencing. Nat. Biotechnol. 38, 954–961 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Ewald, J. D. et al. HumanIslets.com: improving accessibility, integration, and usability of human research islet data. Cell Metab. 37, 7–11 (2025).

Article 
CAS 
PubMed 

Google Scholar 

Cao, Y. et al. Raw images for: Single-cell perturbations decipher ribosomal stress-surveillance regulators in type 2 diabetes. Zenodo https://doi.org/10.5281/zenodo.17163230 (2025).

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