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Tropomyosin 1 genetically constrains in vitro hematopoiesis
BACKGROUND: Identifying causal variants and genes from human genetic studies of hematopoietic traits is important to enumerate basic regulatory mechanisms underlying these traits, and could ultimately augment translational efforts to generate platelets and/or red blood cells in vitro. To identify pu...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227211/ https://www.ncbi.nlm.nih.gov/pubmed/32408895 http://dx.doi.org/10.1186/s12915-020-00783-7 |
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author | Thom, Christopher Stephen Jobaliya, Chintan D Lorenz, Kimberly Maguire, Jean Ann Gagne, Alyssa Gadue, Paul French, Deborah L Voight, Benjamin Franklin |
author_facet | Thom, Christopher Stephen Jobaliya, Chintan D Lorenz, Kimberly Maguire, Jean Ann Gagne, Alyssa Gadue, Paul French, Deborah L Voight, Benjamin Franklin |
author_sort | Thom, Christopher Stephen |
collection | PubMed |
description | BACKGROUND: Identifying causal variants and genes from human genetic studies of hematopoietic traits is important to enumerate basic regulatory mechanisms underlying these traits, and could ultimately augment translational efforts to generate platelets and/or red blood cells in vitro. To identify putative causal genes from these data, we performed computational modeling using available genome-wide association datasets for platelet and red blood cell traits. RESULTS: Our model identified a joint collection of genomic features enriched at established trait associations and plausible candidate variants. Additional studies associating variation at these loci with change in gene expression highlighted Tropomyosin 1 (TPM1) among our top-ranked candidate genes. CRISPR/Cas9-mediated TPM1 knockout in human induced pluripotent stem cells (iPSCs) enhanced hematopoietic progenitor development, increasing total megakaryocyte and erythroid cell yields. CONCLUSIONS: Our findings may help explain human genetic associations and identify a novel genetic strategy to enhance in vitro hematopoiesis. A similar trait-specific gene prioritization strategy could be employed to help streamline functional validation experiments for virtually any human trait. |
format | Online Article Text |
id | pubmed-7227211 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-72272112020-05-27 Tropomyosin 1 genetically constrains in vitro hematopoiesis Thom, Christopher Stephen Jobaliya, Chintan D Lorenz, Kimberly Maguire, Jean Ann Gagne, Alyssa Gadue, Paul French, Deborah L Voight, Benjamin Franklin BMC Biol Research Article BACKGROUND: Identifying causal variants and genes from human genetic studies of hematopoietic traits is important to enumerate basic regulatory mechanisms underlying these traits, and could ultimately augment translational efforts to generate platelets and/or red blood cells in vitro. To identify putative causal genes from these data, we performed computational modeling using available genome-wide association datasets for platelet and red blood cell traits. RESULTS: Our model identified a joint collection of genomic features enriched at established trait associations and plausible candidate variants. Additional studies associating variation at these loci with change in gene expression highlighted Tropomyosin 1 (TPM1) among our top-ranked candidate genes. CRISPR/Cas9-mediated TPM1 knockout in human induced pluripotent stem cells (iPSCs) enhanced hematopoietic progenitor development, increasing total megakaryocyte and erythroid cell yields. CONCLUSIONS: Our findings may help explain human genetic associations and identify a novel genetic strategy to enhance in vitro hematopoiesis. A similar trait-specific gene prioritization strategy could be employed to help streamline functional validation experiments for virtually any human trait. BioMed Central 2020-05-14 /pmc/articles/PMC7227211/ /pubmed/32408895 http://dx.doi.org/10.1186/s12915-020-00783-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Thom, Christopher Stephen Jobaliya, Chintan D Lorenz, Kimberly Maguire, Jean Ann Gagne, Alyssa Gadue, Paul French, Deborah L Voight, Benjamin Franklin Tropomyosin 1 genetically constrains in vitro hematopoiesis |
title | Tropomyosin 1 genetically constrains in vitro hematopoiesis |
title_full | Tropomyosin 1 genetically constrains in vitro hematopoiesis |
title_fullStr | Tropomyosin 1 genetically constrains in vitro hematopoiesis |
title_full_unstemmed | Tropomyosin 1 genetically constrains in vitro hematopoiesis |
title_short | Tropomyosin 1 genetically constrains in vitro hematopoiesis |
title_sort | tropomyosin 1 genetically constrains in vitro hematopoiesis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227211/ https://www.ncbi.nlm.nih.gov/pubmed/32408895 http://dx.doi.org/10.1186/s12915-020-00783-7 |
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