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Title: Stable enhancers are active in development, and fragile enhancers are associated with evolutionary adaptation

Abstract

Background: Despite continual progress in the identification and characterization of trait- and disease-associated variants that disrupt transcription factor (TF)-DNA binding, little is known about the distribution of TF binding deactivating mutations (deMs) in enhancer sequences. Here, we focus on elucidating the mechanism underlying the different densities of deMs in human enhancers. Results: We identify two classes of enhancers based on the density of nucleotides prone to deMs. Firstly, fragile enhancers with abundant deM nucleotides are associated with the immune system and regular cellular maintenance. Secondly, stable enhancers with only a few deM nucleotides are associated with the development and regulation of TFs and are evolutionarily conserved. These two classes of enhancers feature different regulatory programs: the binding sites of pioneer TFs of FOX family are specifically enriched in stable enhancers, while tissue-specific TFs are enriched in fragile enhancers. Moreover, stable enhancers are more tolerant of deMs due to their dominant employment of homotypic TF binding site (TFBS) clusters, as opposed to the larger-extent usage of heterotypic TFBS clusters in fragile enhancers. Notably, the sequence environment and chromatin context of the cognate motif, other than the motif itself, contribute more to the susceptibility to deMs of TF binding. Conclusions: This dichotomymore » of enhancer activity is conserved across different tissues, has a specific footprint in epigenetic profiles, and argues for a bimodal evolution of gene regulatory programs in vertebrates. Specifically encoded stable enhancers are evolutionarily conserved and associated with development, while differently encoded fragile enhancers are associated with the adaptation of species.« less

Authors:
 [1];  [2];  [3];  [4];  [1]
  1. National Inst. of Health (NIH), Bethesda, MD (United States). National Library of Medicine. National Center for Biotechnology Information. Computational Biology Branch
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Joint BioEnergy Institute and Environmental Genomics and Systems Biology Division
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Joint BioEnergy Institute and Environmental Genomics and Systems Biology Division; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Merced, CA (United States). School of Natural Sciences
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Joint BioEnergy Institute and Environmental Genomics and Systems Biology Division; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Berkeley, CA (United States). Comparative Biochemistry Program
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1626946
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Genome Biology (Online)
Additional Journal Information:
Journal Name: Genome Biology (Online); Journal Volume: 20; Journal Issue: 1; Journal ID: ISSN 1474-760X
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biotechnology & Applied Microbiology; Genetics & Heredity; Enhancer; Evolution of gene regulation; Transcription factor interaction; Causal regulatory variants; Transgenic mouse reporter assay

Citation Formats

Li, Shan, Kvon, Evgeny Z., Visel, Axel, Pennacchio, Len A., and Ovcharenko, Ivan. Stable enhancers are active in development, and fragile enhancers are associated with evolutionary adaptation. United States: N. p., 2019. Web. https://doi.org/10.1186/s13059-019-1750-z.
Li, Shan, Kvon, Evgeny Z., Visel, Axel, Pennacchio, Len A., & Ovcharenko, Ivan. Stable enhancers are active in development, and fragile enhancers are associated with evolutionary adaptation. United States. https://doi.org/10.1186/s13059-019-1750-z
Li, Shan, Kvon, Evgeny Z., Visel, Axel, Pennacchio, Len A., and Ovcharenko, Ivan. Mon . "Stable enhancers are active in development, and fragile enhancers are associated with evolutionary adaptation". United States. https://doi.org/10.1186/s13059-019-1750-z. https://www.osti.gov/servlets/purl/1626946.
@article{osti_1626946,
title = {Stable enhancers are active in development, and fragile enhancers are associated with evolutionary adaptation},
author = {Li, Shan and Kvon, Evgeny Z. and Visel, Axel and Pennacchio, Len A. and Ovcharenko, Ivan},
abstractNote = {Background: Despite continual progress in the identification and characterization of trait- and disease-associated variants that disrupt transcription factor (TF)-DNA binding, little is known about the distribution of TF binding deactivating mutations (deMs) in enhancer sequences. Here, we focus on elucidating the mechanism underlying the different densities of deMs in human enhancers. Results: We identify two classes of enhancers based on the density of nucleotides prone to deMs. Firstly, fragile enhancers with abundant deM nucleotides are associated with the immune system and regular cellular maintenance. Secondly, stable enhancers with only a few deM nucleotides are associated with the development and regulation of TFs and are evolutionarily conserved. These two classes of enhancers feature different regulatory programs: the binding sites of pioneer TFs of FOX family are specifically enriched in stable enhancers, while tissue-specific TFs are enriched in fragile enhancers. Moreover, stable enhancers are more tolerant of deMs due to their dominant employment of homotypic TF binding site (TFBS) clusters, as opposed to the larger-extent usage of heterotypic TFBS clusters in fragile enhancers. Notably, the sequence environment and chromatin context of the cognate motif, other than the motif itself, contribute more to the susceptibility to deMs of TF binding. Conclusions: This dichotomy of enhancer activity is conserved across different tissues, has a specific footprint in epigenetic profiles, and argues for a bimodal evolution of gene regulatory programs in vertebrates. Specifically encoded stable enhancers are evolutionarily conserved and associated with development, while differently encoded fragile enhancers are associated with the adaptation of species.},
doi = {10.1186/s13059-019-1750-z},
journal = {Genome Biology (Online)},
number = 1,
volume = 20,
place = {United States},
year = {2019},
month = {7}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Figures / Tables:

Fig. 1 Fig. 1: The two factors of a CAPE score. a The two factors associated with each genetic variant in the classifier: $Δ$, the disruptive effect on the cognate motif caused by a single-nucleotide variant; S, the binding capability of the neighboring region. b The general idea of the CAPE—integration ofmore » two factors ($Δ$ and S) learned from variable enhancer-associated ChIP-seq peaks and DNase to the SVM classifier. Refer to formula 2 in the “Methods” section for the details of parameters« less

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