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Topologically associating domain boundaries are required for normal genome function
Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes(1–3), but the overall extent to which this occurs remains unknown. Her...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119121/ https://www.ncbi.nlm.nih.gov/pubmed/37081156 http://dx.doi.org/10.1038/s42003-023-04819-w |
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author | Rajderkar, Sudha Barozzi, Iros Zhu, Yiwen Hu, Rong Zhang, Yanxiao Li, Bin Alcaina Caro, Ana Fukuda-Yuzawa, Yoko Kelman, Guy Akeza, Adyam Blow, Matthew J. Pham, Quan Harrington, Anne N. Godoy, Janeth Meky, Eman M. von Maydell, Kianna Hunter, Riana D. Akiyama, Jennifer A. Novak, Catherine S. Plajzer-Frick, Ingrid Afzal, Veena Tran, Stella Lopez-Rios, Javier Talkowski, Michael E. Lloyd, K. C. Kent Ren, Bing Dickel, Diane E. Visel, Axel Pennacchio, Len A. |
author_facet | Rajderkar, Sudha Barozzi, Iros Zhu, Yiwen Hu, Rong Zhang, Yanxiao Li, Bin Alcaina Caro, Ana Fukuda-Yuzawa, Yoko Kelman, Guy Akeza, Adyam Blow, Matthew J. Pham, Quan Harrington, Anne N. Godoy, Janeth Meky, Eman M. von Maydell, Kianna Hunter, Riana D. Akiyama, Jennifer A. Novak, Catherine S. Plajzer-Frick, Ingrid Afzal, Veena Tran, Stella Lopez-Rios, Javier Talkowski, Michael E. Lloyd, K. C. Kent Ren, Bing Dickel, Diane E. Visel, Axel Pennacchio, Len A. |
author_sort | Rajderkar, Sudha |
collection | PubMed |
description | Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes(1–3), but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11–80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening. |
format | Online Article Text |
id | pubmed-10119121 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101191212023-04-22 Topologically associating domain boundaries are required for normal genome function Rajderkar, Sudha Barozzi, Iros Zhu, Yiwen Hu, Rong Zhang, Yanxiao Li, Bin Alcaina Caro, Ana Fukuda-Yuzawa, Yoko Kelman, Guy Akeza, Adyam Blow, Matthew J. Pham, Quan Harrington, Anne N. Godoy, Janeth Meky, Eman M. von Maydell, Kianna Hunter, Riana D. Akiyama, Jennifer A. Novak, Catherine S. Plajzer-Frick, Ingrid Afzal, Veena Tran, Stella Lopez-Rios, Javier Talkowski, Michael E. Lloyd, K. C. Kent Ren, Bing Dickel, Diane E. Visel, Axel Pennacchio, Len A. Commun Biol Article Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes(1–3), but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11–80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening. Nature Publishing Group UK 2023-04-20 /pmc/articles/PMC10119121/ /pubmed/37081156 http://dx.doi.org/10.1038/s42003-023-04819-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Rajderkar, Sudha Barozzi, Iros Zhu, Yiwen Hu, Rong Zhang, Yanxiao Li, Bin Alcaina Caro, Ana Fukuda-Yuzawa, Yoko Kelman, Guy Akeza, Adyam Blow, Matthew J. Pham, Quan Harrington, Anne N. Godoy, Janeth Meky, Eman M. von Maydell, Kianna Hunter, Riana D. Akiyama, Jennifer A. Novak, Catherine S. Plajzer-Frick, Ingrid Afzal, Veena Tran, Stella Lopez-Rios, Javier Talkowski, Michael E. Lloyd, K. C. Kent Ren, Bing Dickel, Diane E. Visel, Axel Pennacchio, Len A. Topologically associating domain boundaries are required for normal genome function |
title | Topologically associating domain boundaries are required for normal genome function |
title_full | Topologically associating domain boundaries are required for normal genome function |
title_fullStr | Topologically associating domain boundaries are required for normal genome function |
title_full_unstemmed | Topologically associating domain boundaries are required for normal genome function |
title_short | Topologically associating domain boundaries are required for normal genome function |
title_sort | topologically associating domain boundaries are required for normal genome function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119121/ https://www.ncbi.nlm.nih.gov/pubmed/37081156 http://dx.doi.org/10.1038/s42003-023-04819-w |
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