Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function

Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, genera...

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Veröffentlicht in:	Science (American Association for the Advancement of Science) Jg. 376; H. 6594; S. eabl4290
Hauptverfasser:	Eraslan, Gökcen, Drokhlyansky, Eugene, Anand, Shankara, Fiskin, Evgenij, Subramanian, Ayshwarya, Slyper, Michal, Wang, Jiali, Van Wittenberghe, Nicholas, Rouhana, John M, Waldman, Julia, Ashenberg, Orr, Lek, Monkol, Dionne, Danielle, Win, Thet Su, Cuoco, Michael S, Kuksenko, Olena, Tsankov, Alexander M, Branton, Philip A, Marshall, Jamie L, Greka, Anna, Getz, Gad, Segrè, Ayellet V, Aguet, François, Rozenblatt-Rosen, Orit, Ardlie, Kristin G, Regev, Aviv
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 13.05.2022
Schlagworte:	Biomarkers Cell Nucleus - genetics Disease - genetics Genome-Wide Association Study Humans Organ Specificity Phenotype RNA-Seq - methods
ISSN:	1095-9203, 1095-9203
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Abstract	Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.
AbstractList	Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies. Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.
Author	Drokhlyansky, Eugene Rouhana, John M Slyper, Michal Dionne, Danielle Tsankov, Alexander M Eraslan, Gökcen Segrè, Ayellet V Anand, Shankara Wang, Jiali Ardlie, Kristin G Cuoco, Michael S Kuksenko, Olena Subramanian, Ayshwarya Van Wittenberghe, Nicholas Win, Thet Su Ashenberg, Orr Regev, Aviv Lek, Monkol Aguet, François Fiskin, Evgenij Branton, Philip A Rozenblatt-Rosen, Orit Greka, Anna Waldman, Julia Getz, Gad Marshall, Jamie L
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and Harvard, Cambridge, MA 02142, USA – sequence: 6 givenname: Michal orcidid: 0000-0002-3002-0366 surname: Slyper fullname: Slyper, Michal organization: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 7 givenname: Jiali orcidid: 0000-0002-4459-9284 surname: Wang fullname: Wang, Jiali organization: Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 8 givenname: Nicholas orcidid: 0000-0002-7653-9729 surname: Van Wittenberghe fullname: Van Wittenberghe, Nicholas organization: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 9 givenname: John M surname: Rouhana fullname: Rouhana, John M organization: Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 10 givenname: Julia orcidid: 0000-0002-0584-5833 surname: Waldman fullname: Waldman, Julia organization: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 11 givenname: Orr orcidid: 0000-0002-7802-8834 surname: Ashenberg fullname: Ashenberg, Orr organization: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 12 givenname: Monkol surname: Lek fullname: Lek, Monkol organization: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA – sequence: 13 givenname: Danielle orcidid: 0000-0002-8338-4323 surname: Dionne fullname: Dionne, Danielle organization: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 14 givenname: Thet Su surname: Win fullname: Win, Thet Su organization: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA – sequence: 15 givenname: Michael S orcidid: 0000-0003-2163-5120 surname: Cuoco fullname: Cuoco, Michael S organization: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 16 givenname: Olena orcidid: 0000-0002-1728-4957 surname: Kuksenko fullname: Kuksenko, Olena organization: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 17 givenname: Alexander M orcidid: 0000-0002-7955-4414 surname: Tsankov fullname: Tsankov, Alexander M organization: Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – sequence: 18 givenname: Philip A orcidid: 0000-0002-0898-9605 surname: Branton fullname: Branton, Philip A organization: The Joint Pathology Center Gynecologic/Breast Pathology, Silver Spring, MD 20910, USA – sequence: 19 givenname: Jamie L orcidid: 0000-0002-2364-391X surname: Marshall fullname: Marshall, Jamie L organization: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 20 givenname: Anna orcidid: 0000-0001-5697-7791 surname: Greka fullname: Greka, Anna organization: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA – sequence: 21 givenname: Gad orcidid: 0000-0002-0936-0753 surname: Getz fullname: Getz, Gad organization: Harvard Medical School, Boston, MA 02115, USA – sequence: 22 givenname: Ayellet V orcidid: 0000-0001-6806-5845 surname: Segrè fullname: Segrè, Ayellet V organization: Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 23 givenname: François orcidid: 0000-0001-9414-300X surname: Aguet fullname: Aguet, François organization: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 24 givenname: Orit orcidid: 0000-0001-6313-3570 surname: Rozenblatt-Rosen fullname: Rozenblatt-Rosen, Orit organization: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 25 givenname: Kristin G orcidid: 0000-0003-4272-6283 surname: Ardlie fullname: Ardlie, Kristin G organization: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 26 givenname: Aviv orcidid: 0000-0003-3293-3158 surname: Regev fullname: Regev, Aviv organization: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/35549429$$D View this record in MEDLINE/PubMed
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References	35549410 - Science. 2022 May 13;376(6594):695-696 36039543 - Am J Transplant. 2022 Sep;22(9):2127-2128 36198687 - Signal Transduct Target Ther. 2022 Oct 5;7(1):352
References_xml	– reference: 35549410 - Science. 2022 May 13;376(6594):695-696 – reference: 36198687 - Signal Transduct Target Ther. 2022 Oct 5;7(1):352 – reference: 36039543 - Am J Transplant. 2022 Sep;22(9):2127-2128
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Snippet	Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed....
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SubjectTerms	Biomarkers Cell Nucleus - genetics Disease - genetics Genome-Wide Association Study Humans Organ Specificity Phenotype RNA-Seq - methods
Title	Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function
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