Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A
Abstract Broad heterogeneity in pancreatic β-cell function and morphology has been widely reported. However, determining which components of this cellular heterogeneity serve a diabetes-relevant function remains challenging. Here, we integrate single-cell transcriptome, single-nuclei chromatin acces...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41228-3 |
| _version_ | 1797558118874349568 |
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| author | Chen Weng Anniya Gu Shanshan Zhang Leina Lu Luxin Ke Peidong Gao Xiaoxiao Liu Yuntong Wang Peinan Hu Dylan Plummer Elise MacDonald Saixian Zhang Jiajia Xi Sisi Lai Konstantin Leskov Kyle Yuan Fulai Jin Yan Li |
| author_facet | Chen Weng Anniya Gu Shanshan Zhang Leina Lu Luxin Ke Peidong Gao Xiaoxiao Liu Yuntong Wang Peinan Hu Dylan Plummer Elise MacDonald Saixian Zhang Jiajia Xi Sisi Lai Konstantin Leskov Kyle Yuan Fulai Jin Yan Li |
| author_sort | Chen Weng |
| collection | DOAJ |
| description | Abstract Broad heterogeneity in pancreatic β-cell function and morphology has been widely reported. However, determining which components of this cellular heterogeneity serve a diabetes-relevant function remains challenging. Here, we integrate single-cell transcriptome, single-nuclei chromatin accessibility, and cell-type specific 3D genome profiles from human islets and identify Type II Diabetes (T2D)-associated β-cell heterogeneity at both transcriptomic and epigenomic levels. We develop a computational method to explicitly dissect the intra-donor and inter-donor heterogeneity between single β-cells, which reflect distinct mechanisms of T2D pathogenesis. Integrative transcriptomic and epigenomic analysis identifies HNF1A as a principal driver of intra-donor heterogeneity between β-cells from the same donors; HNF1A expression is also reduced in β-cells from T2D donors. Interestingly, HNF1A activity in single β-cells is significantly associated with lower Na+ currents and we nominate a HNF1A target, FXYD2, as the primary mitigator. Our study demonstrates the value of investigating disease-associated single-cell heterogeneity and provides new insights into the pathogenesis of T2D. |
| first_indexed | 2024-03-10T17:25:56Z |
| format | Article |
| id | doaj.art-09fc53eb3601471c88388c09e803f66e |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:25:56Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-09fc53eb3601471c88388c09e803f66e2023-11-20T10:09:06ZengNature PortfolioNature Communications2041-17232023-09-0114111710.1038/s41467-023-41228-3Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1AChen Weng0Anniya Gu1Shanshan Zhang2Leina Lu3Luxin Ke4Peidong Gao5Xiaoxiao Liu6Yuntong Wang7Peinan Hu8Dylan Plummer9Elise MacDonald10Saixian Zhang11Jiajia Xi12Sisi Lai13Konstantin Leskov14Kyle Yuan15Fulai Jin16Yan Li17Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Computer and Data Sciences, School of Engineering, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityAbstract Broad heterogeneity in pancreatic β-cell function and morphology has been widely reported. However, determining which components of this cellular heterogeneity serve a diabetes-relevant function remains challenging. Here, we integrate single-cell transcriptome, single-nuclei chromatin accessibility, and cell-type specific 3D genome profiles from human islets and identify Type II Diabetes (T2D)-associated β-cell heterogeneity at both transcriptomic and epigenomic levels. We develop a computational method to explicitly dissect the intra-donor and inter-donor heterogeneity between single β-cells, which reflect distinct mechanisms of T2D pathogenesis. Integrative transcriptomic and epigenomic analysis identifies HNF1A as a principal driver of intra-donor heterogeneity between β-cells from the same donors; HNF1A expression is also reduced in β-cells from T2D donors. Interestingly, HNF1A activity in single β-cells is significantly associated with lower Na+ currents and we nominate a HNF1A target, FXYD2, as the primary mitigator. Our study demonstrates the value of investigating disease-associated single-cell heterogeneity and provides new insights into the pathogenesis of T2D.https://doi.org/10.1038/s41467-023-41228-3 |
| spellingShingle | Chen Weng Anniya Gu Shanshan Zhang Leina Lu Luxin Ke Peidong Gao Xiaoxiao Liu Yuntong Wang Peinan Hu Dylan Plummer Elise MacDonald Saixian Zhang Jiajia Xi Sisi Lai Konstantin Leskov Kyle Yuan Fulai Jin Yan Li Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A Nature Communications |
| title | Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A |
| title_full | Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A |
| title_fullStr | Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A |
| title_full_unstemmed | Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A |
| title_short | Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A |
| title_sort | single cell multiomic analysis reveals diabetes associated β cell heterogeneity driven by hnf1a |
| url | https://doi.org/10.1038/s41467-023-41228-3 |
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