Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary
Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chr...
Ausführliche Beschreibung
Autor*in: |
Matt Kanke [verfasserIn] Meaghan M. Kennedy Ng [verfasserIn] Sean Connelly [verfasserIn] Manvendra Singh [verfasserIn] Matthew Schaner [verfasserIn] Michael T. Shanahan [verfasserIn] Elizabeth A. Wolber [verfasserIn] Caroline Beasley [verfasserIn] Grace Lian [verfasserIn] Animesh Jain [verfasserIn] Millie D. Long [verfasserIn] Edward L. Barnes [verfasserIn] Hans H. Herfarth [verfasserIn] Kim L. Isaacs [verfasserIn] Jonathon J. Hansen [verfasserIn] Muneera Kapadia [verfasserIn] Jose Gaston Guillem [verfasserIn] Cedric Feschotte [verfasserIn] Terrence S. Furey [verfasserIn] Shehzad Z. Sheikh [verfasserIn] Praveen Sethupathy [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2022 |
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Übergeordnetes Werk: |
In: Cellular and Molecular Gastroenterology and Hepatology - Elsevier, 2017, 13(2022), 6, Seite 1717-1740 |
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Übergeordnetes Werk: |
volume:13 ; year:2022 ; number:6 ; pages:1717-1740 |
Links: |
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DOI / URN: |
10.1016/j.jcmgh.2022.02.005 |
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Katalog-ID: |
DOAJ029561612 |
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245 | 1 | 0 | |a Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary |
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520 | |a Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. | ||
650 | 4 | |a Crohn’s Disease | |
650 | 4 | |a Single-Cell | |
650 | 4 | |a Epithelium | |
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653 | 0 | |a Diseases of the digestive system. Gastroenterology | |
700 | 0 | |a Meaghan M. Kennedy Ng |e verfasserin |4 aut | |
700 | 0 | |a Sean Connelly |e verfasserin |4 aut | |
700 | 0 | |a Manvendra Singh |e verfasserin |4 aut | |
700 | 0 | |a Matthew Schaner |e verfasserin |4 aut | |
700 | 0 | |a Michael T. Shanahan |e verfasserin |4 aut | |
700 | 0 | |a Elizabeth A. Wolber |e verfasserin |4 aut | |
700 | 0 | |a Caroline Beasley |e verfasserin |4 aut | |
700 | 0 | |a Grace Lian |e verfasserin |4 aut | |
700 | 0 | |a Animesh Jain |e verfasserin |4 aut | |
700 | 0 | |a Millie D. Long |e verfasserin |4 aut | |
700 | 0 | |a Edward L. Barnes |e verfasserin |4 aut | |
700 | 0 | |a Hans H. Herfarth |e verfasserin |4 aut | |
700 | 0 | |a Kim L. Isaacs |e verfasserin |4 aut | |
700 | 0 | |a Jonathon J. Hansen |e verfasserin |4 aut | |
700 | 0 | |a Muneera Kapadia |e verfasserin |4 aut | |
700 | 0 | |a Jose Gaston Guillem |e verfasserin |4 aut | |
700 | 0 | |a Cedric Feschotte |e verfasserin |4 aut | |
700 | 0 | |a Terrence S. Furey |e verfasserin |4 aut | |
700 | 0 | |a Shehzad Z. Sheikh |e verfasserin |4 aut | |
700 | 0 | |a Praveen Sethupathy |e verfasserin |4 aut | |
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10.1016/j.jcmgh.2022.02.005 doi (DE-627)DOAJ029561612 (DE-599)DOAJf26eceddd75d46159db62af17e2aa45c DE-627 ger DE-627 rakwb eng RC799-869 Matt Kanke verfasserin aut Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. Crohn’s Disease Single-Cell Epithelium Colonocyte Gene Expression ISC Diseases of the digestive system. Gastroenterology Meaghan M. Kennedy Ng verfasserin aut Sean Connelly verfasserin aut Manvendra Singh verfasserin aut Matthew Schaner verfasserin aut Michael T. Shanahan verfasserin aut Elizabeth A. Wolber verfasserin aut Caroline Beasley verfasserin aut Grace Lian verfasserin aut Animesh Jain verfasserin aut Millie D. Long verfasserin aut Edward L. Barnes verfasserin aut Hans H. Herfarth verfasserin aut Kim L. Isaacs verfasserin aut Jonathon J. Hansen verfasserin aut Muneera Kapadia verfasserin aut Jose Gaston Guillem verfasserin aut Cedric Feschotte verfasserin aut Terrence S. Furey verfasserin aut Shehzad Z. Sheikh verfasserin aut Praveen Sethupathy verfasserin aut In Cellular and Molecular Gastroenterology and Hepatology Elsevier, 2017 13(2022), 6, Seite 1717-1740 (DE-627)823790088 (DE-600)2819778-1 2352345X nnns volume:13 year:2022 number:6 pages:1717-1740 https://doi.org/10.1016/j.jcmgh.2022.02.005 kostenfrei https://doaj.org/article/f26eceddd75d46159db62af17e2aa45c kostenfrei http://www.sciencedirect.com/science/article/pii/S2352345X22000327 kostenfrei https://doaj.org/toc/2352-345X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 13 2022 6 1717-1740 |
spelling |
10.1016/j.jcmgh.2022.02.005 doi (DE-627)DOAJ029561612 (DE-599)DOAJf26eceddd75d46159db62af17e2aa45c DE-627 ger DE-627 rakwb eng RC799-869 Matt Kanke verfasserin aut Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. Crohn’s Disease Single-Cell Epithelium Colonocyte Gene Expression ISC Diseases of the digestive system. Gastroenterology Meaghan M. Kennedy Ng verfasserin aut Sean Connelly verfasserin aut Manvendra Singh verfasserin aut Matthew Schaner verfasserin aut Michael T. Shanahan verfasserin aut Elizabeth A. Wolber verfasserin aut Caroline Beasley verfasserin aut Grace Lian verfasserin aut Animesh Jain verfasserin aut Millie D. Long verfasserin aut Edward L. Barnes verfasserin aut Hans H. Herfarth verfasserin aut Kim L. Isaacs verfasserin aut Jonathon J. Hansen verfasserin aut Muneera Kapadia verfasserin aut Jose Gaston Guillem verfasserin aut Cedric Feschotte verfasserin aut Terrence S. Furey verfasserin aut Shehzad Z. Sheikh verfasserin aut Praveen Sethupathy verfasserin aut In Cellular and Molecular Gastroenterology and Hepatology Elsevier, 2017 13(2022), 6, Seite 1717-1740 (DE-627)823790088 (DE-600)2819778-1 2352345X nnns volume:13 year:2022 number:6 pages:1717-1740 https://doi.org/10.1016/j.jcmgh.2022.02.005 kostenfrei https://doaj.org/article/f26eceddd75d46159db62af17e2aa45c kostenfrei http://www.sciencedirect.com/science/article/pii/S2352345X22000327 kostenfrei https://doaj.org/toc/2352-345X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 13 2022 6 1717-1740 |
allfields_unstemmed |
10.1016/j.jcmgh.2022.02.005 doi (DE-627)DOAJ029561612 (DE-599)DOAJf26eceddd75d46159db62af17e2aa45c DE-627 ger DE-627 rakwb eng RC799-869 Matt Kanke verfasserin aut Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. Crohn’s Disease Single-Cell Epithelium Colonocyte Gene Expression ISC Diseases of the digestive system. Gastroenterology Meaghan M. Kennedy Ng verfasserin aut Sean Connelly verfasserin aut Manvendra Singh verfasserin aut Matthew Schaner verfasserin aut Michael T. Shanahan verfasserin aut Elizabeth A. Wolber verfasserin aut Caroline Beasley verfasserin aut Grace Lian verfasserin aut Animesh Jain verfasserin aut Millie D. Long verfasserin aut Edward L. Barnes verfasserin aut Hans H. Herfarth verfasserin aut Kim L. Isaacs verfasserin aut Jonathon J. Hansen verfasserin aut Muneera Kapadia verfasserin aut Jose Gaston Guillem verfasserin aut Cedric Feschotte verfasserin aut Terrence S. Furey verfasserin aut Shehzad Z. Sheikh verfasserin aut Praveen Sethupathy verfasserin aut In Cellular and Molecular Gastroenterology and Hepatology Elsevier, 2017 13(2022), 6, Seite 1717-1740 (DE-627)823790088 (DE-600)2819778-1 2352345X nnns volume:13 year:2022 number:6 pages:1717-1740 https://doi.org/10.1016/j.jcmgh.2022.02.005 kostenfrei https://doaj.org/article/f26eceddd75d46159db62af17e2aa45c kostenfrei http://www.sciencedirect.com/science/article/pii/S2352345X22000327 kostenfrei https://doaj.org/toc/2352-345X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 13 2022 6 1717-1740 |
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10.1016/j.jcmgh.2022.02.005 doi (DE-627)DOAJ029561612 (DE-599)DOAJf26eceddd75d46159db62af17e2aa45c DE-627 ger DE-627 rakwb eng RC799-869 Matt Kanke verfasserin aut Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. Crohn’s Disease Single-Cell Epithelium Colonocyte Gene Expression ISC Diseases of the digestive system. Gastroenterology Meaghan M. Kennedy Ng verfasserin aut Sean Connelly verfasserin aut Manvendra Singh verfasserin aut Matthew Schaner verfasserin aut Michael T. Shanahan verfasserin aut Elizabeth A. Wolber verfasserin aut Caroline Beasley verfasserin aut Grace Lian verfasserin aut Animesh Jain verfasserin aut Millie D. Long verfasserin aut Edward L. Barnes verfasserin aut Hans H. Herfarth verfasserin aut Kim L. Isaacs verfasserin aut Jonathon J. Hansen verfasserin aut Muneera Kapadia verfasserin aut Jose Gaston Guillem verfasserin aut Cedric Feschotte verfasserin aut Terrence S. Furey verfasserin aut Shehzad Z. Sheikh verfasserin aut Praveen Sethupathy verfasserin aut In Cellular and Molecular Gastroenterology and Hepatology Elsevier, 2017 13(2022), 6, Seite 1717-1740 (DE-627)823790088 (DE-600)2819778-1 2352345X nnns volume:13 year:2022 number:6 pages:1717-1740 https://doi.org/10.1016/j.jcmgh.2022.02.005 kostenfrei https://doaj.org/article/f26eceddd75d46159db62af17e2aa45c kostenfrei http://www.sciencedirect.com/science/article/pii/S2352345X22000327 kostenfrei https://doaj.org/toc/2352-345X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 13 2022 6 1717-1740 |
allfieldsSound |
10.1016/j.jcmgh.2022.02.005 doi (DE-627)DOAJ029561612 (DE-599)DOAJf26eceddd75d46159db62af17e2aa45c DE-627 ger DE-627 rakwb eng RC799-869 Matt Kanke verfasserin aut Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. Crohn’s Disease Single-Cell Epithelium Colonocyte Gene Expression ISC Diseases of the digestive system. Gastroenterology Meaghan M. Kennedy Ng verfasserin aut Sean Connelly verfasserin aut Manvendra Singh verfasserin aut Matthew Schaner verfasserin aut Michael T. Shanahan verfasserin aut Elizabeth A. Wolber verfasserin aut Caroline Beasley verfasserin aut Grace Lian verfasserin aut Animesh Jain verfasserin aut Millie D. Long verfasserin aut Edward L. Barnes verfasserin aut Hans H. Herfarth verfasserin aut Kim L. Isaacs verfasserin aut Jonathon J. Hansen verfasserin aut Muneera Kapadia verfasserin aut Jose Gaston Guillem verfasserin aut Cedric Feschotte verfasserin aut Terrence S. Furey verfasserin aut Shehzad Z. Sheikh verfasserin aut Praveen Sethupathy verfasserin aut In Cellular and Molecular Gastroenterology and Hepatology Elsevier, 2017 13(2022), 6, Seite 1717-1740 (DE-627)823790088 (DE-600)2819778-1 2352345X nnns volume:13 year:2022 number:6 pages:1717-1740 https://doi.org/10.1016/j.jcmgh.2022.02.005 kostenfrei https://doaj.org/article/f26eceddd75d46159db62af17e2aa45c kostenfrei http://www.sciencedirect.com/science/article/pii/S2352345X22000327 kostenfrei https://doaj.org/toc/2352-345X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 13 2022 6 1717-1740 |
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Matt Kanke @@aut@@ Meaghan M. Kennedy Ng @@aut@@ Sean Connelly @@aut@@ Manvendra Singh @@aut@@ Matthew Schaner @@aut@@ Michael T. Shanahan @@aut@@ Elizabeth A. Wolber @@aut@@ Caroline Beasley @@aut@@ Grace Lian @@aut@@ Animesh Jain @@aut@@ Millie D. Long @@aut@@ Edward L. Barnes @@aut@@ Hans H. Herfarth @@aut@@ Kim L. Isaacs @@aut@@ Jonathon J. Hansen @@aut@@ Muneera Kapadia @@aut@@ Jose Gaston Guillem @@aut@@ Cedric Feschotte @@aut@@ Terrence S. Furey @@aut@@ Shehzad Z. Sheikh @@aut@@ Praveen Sethupathy @@aut@@ |
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Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. 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Matt Kanke misc RC799-869 misc Crohn’s Disease misc Single-Cell misc Epithelium misc Colonocyte misc Gene Expression misc ISC misc Diseases of the digestive system. Gastroenterology Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary |
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RC799-869 Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary Crohn’s Disease Single-Cell Epithelium Colonocyte Gene Expression ISC |
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Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary |
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Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary |
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Matt Kanke Meaghan M. Kennedy Ng Sean Connelly Manvendra Singh Matthew Schaner Michael T. Shanahan Elizabeth A. Wolber Caroline Beasley Grace Lian Animesh Jain Millie D. Long Edward L. Barnes Hans H. Herfarth Kim L. Isaacs Jonathon J. Hansen Muneera Kapadia Jose Gaston Guillem Cedric Feschotte Terrence S. Furey Shehzad Z. Sheikh Praveen Sethupathy |
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single-cell analysis reveals unexpected cellular changes and transposon expression signatures in the colonic epithelium of treatment-naïve adult crohn’s disease patientssummary |
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Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary |
abstract |
Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. |
abstractGer |
Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. |
abstract_unstemmed |
Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD. |
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Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary |
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Meaghan M. Kennedy Ng Sean Connelly Manvendra Singh Matthew Schaner Michael T. Shanahan Elizabeth A. Wolber Caroline Beasley Grace Lian Animesh Jain Millie D. Long Edward L. Barnes Hans H. Herfarth Kim L. Isaacs Jonathon J. Hansen Muneera Kapadia Jose Gaston Guillem Cedric Feschotte Terrence S. Furey Shehzad Z. Sheikh Praveen Sethupathy |
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Meaghan M. Kennedy Ng Sean Connelly Manvendra Singh Matthew Schaner Michael T. Shanahan Elizabeth A. Wolber Caroline Beasley Grace Lian Animesh Jain Millie D. Long Edward L. Barnes Hans H. Herfarth Kim L. Isaacs Jonathon J. Hansen Muneera Kapadia Jose Gaston Guillem Cedric Feschotte Terrence S. Furey Shehzad Z. Sheikh Praveen Sethupathy |
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Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. 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