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Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs
Regulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance o...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809895/ https://www.ncbi.nlm.nih.gov/pubmed/35049498 http://dx.doi.org/10.7554/eLife.70878 |
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author | Shen, Zeyang Li, Rick Z Prohaska, Thomas A Hoeksema, Marten A Spann, Nathan J Tao, Jenhan Fonseca, Gregory J Le, Thomas Stolze, Lindsey K Sakai, Mashito Romanoski, Casey E Glass, Christopher K |
author_facet | Shen, Zeyang Li, Rick Z Prohaska, Thomas A Hoeksema, Marten A Spann, Nathan J Tao, Jenhan Fonseca, Gregory J Le, Thomas Stolze, Lindsey K Sakai, Mashito Romanoski, Casey E Glass, Christopher K |
author_sort | Shen, Zeyang |
collection | PubMed |
description | Regulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of TF spacing alterations resulting from naturally occurring insertions and deletions (InDels) has not been systematically analyzed. To address this question, we first characterized the genome-wide spacing relationships of 73 TFs in human K562 cells as determined by ChIP-seq (chromatin immunoprecipitation sequencing). We found a dominant pattern of a relaxed range of spacing between collaborative factors, including 45 TFs exclusively exhibiting relaxed spacing with their binding partners. Next, we exploited millions of InDels provided by genetically diverse mouse strains and human individuals to investigate the effects of altered spacing on TF binding and local histone acetylation. These analyses suggested that spacing alterations resulting from naturally occurring InDels are generally tolerated in comparison to genetic variants directly affecting TF binding sites. To experimentally validate this prediction, we introduced synthetic spacing alterations between PU.1 and C/EBPβ binding sites at six endogenous genomic loci in a macrophage cell line. Remarkably, collaborative binding of PU.1 and C/EBPβ at these locations tolerated changes in spacing ranging from 5 bp increase to >30 bp decrease. Collectively, these findings have implications for understanding mechanisms underlying enhancer selection and for the interpretation of non-coding genetic variation. |
format | Online Article Text |
id | pubmed-8809895 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-88098952022-02-04 Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs Shen, Zeyang Li, Rick Z Prohaska, Thomas A Hoeksema, Marten A Spann, Nathan J Tao, Jenhan Fonseca, Gregory J Le, Thomas Stolze, Lindsey K Sakai, Mashito Romanoski, Casey E Glass, Christopher K eLife Chromosomes and Gene Expression Regulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of TF spacing alterations resulting from naturally occurring insertions and deletions (InDels) has not been systematically analyzed. To address this question, we first characterized the genome-wide spacing relationships of 73 TFs in human K562 cells as determined by ChIP-seq (chromatin immunoprecipitation sequencing). We found a dominant pattern of a relaxed range of spacing between collaborative factors, including 45 TFs exclusively exhibiting relaxed spacing with their binding partners. Next, we exploited millions of InDels provided by genetically diverse mouse strains and human individuals to investigate the effects of altered spacing on TF binding and local histone acetylation. These analyses suggested that spacing alterations resulting from naturally occurring InDels are generally tolerated in comparison to genetic variants directly affecting TF binding sites. To experimentally validate this prediction, we introduced synthetic spacing alterations between PU.1 and C/EBPβ binding sites at six endogenous genomic loci in a macrophage cell line. Remarkably, collaborative binding of PU.1 and C/EBPβ at these locations tolerated changes in spacing ranging from 5 bp increase to >30 bp decrease. Collectively, these findings have implications for understanding mechanisms underlying enhancer selection and for the interpretation of non-coding genetic variation. eLife Sciences Publications, Ltd 2022-01-20 /pmc/articles/PMC8809895/ /pubmed/35049498 http://dx.doi.org/10.7554/eLife.70878 Text en © 2022, Shen et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Chromosomes and Gene Expression Shen, Zeyang Li, Rick Z Prohaska, Thomas A Hoeksema, Marten A Spann, Nathan J Tao, Jenhan Fonseca, Gregory J Le, Thomas Stolze, Lindsey K Sakai, Mashito Romanoski, Casey E Glass, Christopher K Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs |
title | Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs |
title_full | Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs |
title_fullStr | Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs |
title_full_unstemmed | Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs |
title_short | Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs |
title_sort | systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs |
topic | Chromosomes and Gene Expression |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809895/ https://www.ncbi.nlm.nih.gov/pubmed/35049498 http://dx.doi.org/10.7554/eLife.70878 |
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