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Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation

BACKGROUND: Ubiquitously expressed CTCF is involved in numerous cellular functions, such as organizing chromatin into TAD structures. In contrast, its paralog, CTCFL, is normally only present in the testis. However, it is also aberrantly expressed in many cancers. While it is known that shared and u...

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Autores principales: Nishana, Mayilaadumveettil, Ha, Caryn, Rodriguez-Hernaez, Javier, Ranjbaran, Ali, Chio, Erica, Nora, Elphege P., Badri, Sana B., Kloetgen, Andreas, Bruneau, Benoit G., Tsirigos, Aristotelis, Skok, Jane A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212617/
https://www.ncbi.nlm.nih.gov/pubmed/32393311
http://dx.doi.org/10.1186/s13059-020-02024-0
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author Nishana, Mayilaadumveettil
Ha, Caryn
Rodriguez-Hernaez, Javier
Ranjbaran, Ali
Chio, Erica
Nora, Elphege P.
Badri, Sana B.
Kloetgen, Andreas
Bruneau, Benoit G.
Tsirigos, Aristotelis
Skok, Jane A.
author_facet Nishana, Mayilaadumveettil
Ha, Caryn
Rodriguez-Hernaez, Javier
Ranjbaran, Ali
Chio, Erica
Nora, Elphege P.
Badri, Sana B.
Kloetgen, Andreas
Bruneau, Benoit G.
Tsirigos, Aristotelis
Skok, Jane A.
author_sort Nishana, Mayilaadumveettil
collection PubMed
description BACKGROUND: Ubiquitously expressed CTCF is involved in numerous cellular functions, such as organizing chromatin into TAD structures. In contrast, its paralog, CTCFL, is normally only present in the testis. However, it is also aberrantly expressed in many cancers. While it is known that shared and unique zinc finger sequences in CTCF and CTCFL enable CTCFL to bind competitively to a subset of CTCF binding sites as well as its own unique locations, the impact of CTCFL on chromosome organization and gene expression has not been comprehensively analyzed in the context of CTCF function. Using an inducible complementation system, we analyze the impact of expressing CTCFL and CTCF-CTCFL chimeric proteins in the presence or absence of endogenous CTCF to clarify the relative and combined contribution of CTCF and CTCFL to chromosome organization and transcription. RESULTS: We demonstrate that the N terminus of CTCF interacts with cohesin which explains the requirement for convergent CTCF binding sites in loop formation. By analyzing CTCF and CTCFL binding in tandem, we identify phenotypically distinct sites with respect to motifs, targeting to promoter/intronic intergenic regions and chromatin folding. Finally, we reveal that the N, C, and zinc finger terminal domains play unique roles in targeting each paralog to distinct binding sites to regulate transcription, chromatin looping, and insulation. CONCLUSION: This study clarifies the unique and combined contribution of CTCF and CTCFL to chromosome organization and transcription, with direct implications for understanding how their co-expression deregulates transcription in cancer. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this papers at 10.1186/s13059-020-02024-0.
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spelling pubmed-72126172020-05-18 Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation Nishana, Mayilaadumveettil Ha, Caryn Rodriguez-Hernaez, Javier Ranjbaran, Ali Chio, Erica Nora, Elphege P. Badri, Sana B. Kloetgen, Andreas Bruneau, Benoit G. Tsirigos, Aristotelis Skok, Jane A. Genome Biol Research BACKGROUND: Ubiquitously expressed CTCF is involved in numerous cellular functions, such as organizing chromatin into TAD structures. In contrast, its paralog, CTCFL, is normally only present in the testis. However, it is also aberrantly expressed in many cancers. While it is known that shared and unique zinc finger sequences in CTCF and CTCFL enable CTCFL to bind competitively to a subset of CTCF binding sites as well as its own unique locations, the impact of CTCFL on chromosome organization and gene expression has not been comprehensively analyzed in the context of CTCF function. Using an inducible complementation system, we analyze the impact of expressing CTCFL and CTCF-CTCFL chimeric proteins in the presence or absence of endogenous CTCF to clarify the relative and combined contribution of CTCF and CTCFL to chromosome organization and transcription. RESULTS: We demonstrate that the N terminus of CTCF interacts with cohesin which explains the requirement for convergent CTCF binding sites in loop formation. By analyzing CTCF and CTCFL binding in tandem, we identify phenotypically distinct sites with respect to motifs, targeting to promoter/intronic intergenic regions and chromatin folding. Finally, we reveal that the N, C, and zinc finger terminal domains play unique roles in targeting each paralog to distinct binding sites to regulate transcription, chromatin looping, and insulation. CONCLUSION: This study clarifies the unique and combined contribution of CTCF and CTCFL to chromosome organization and transcription, with direct implications for understanding how their co-expression deregulates transcription in cancer. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this papers at 10.1186/s13059-020-02024-0. BioMed Central 2020-05-11 /pmc/articles/PMC7212617/ /pubmed/32393311 http://dx.doi.org/10.1186/s13059-020-02024-0 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
Nishana, Mayilaadumveettil
Ha, Caryn
Rodriguez-Hernaez, Javier
Ranjbaran, Ali
Chio, Erica
Nora, Elphege P.
Badri, Sana B.
Kloetgen, Andreas
Bruneau, Benoit G.
Tsirigos, Aristotelis
Skok, Jane A.
Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation
title Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation
title_full Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation
title_fullStr Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation
title_full_unstemmed Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation
title_short Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation
title_sort defining the relative and combined contribution of ctcf and ctcfl to genomic regulation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212617/
https://www.ncbi.nlm.nih.gov/pubmed/32393311
http://dx.doi.org/10.1186/s13059-020-02024-0
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