Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
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
_version_ 1784644121120473088
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
work_keys_str_mv AT shenzeyang systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT lirickz systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT prohaskathomasa systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT hoeksemamartena systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT spannnathanj systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT taojenhan systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT fonsecagregoryj systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT lethomas systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT stolzelindseyk systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT sakaimashito systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT romanoskicaseye systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs
AT glasschristopherk systematicanalysisofnaturallyoccurringinsertionsanddeletionsthataltertranscriptionfactorspacingidentifiestolerantandsensitivetranscriptionfactorpairs