Single-nucleotide variants within heart enhancers increase binding affinity and disrupt heart development.

Humans Enhancer Elements, Genetic / genetics Induced Pluripotent Stem Cells Myocytes, Cardiac / metabolism Binding Sites Nucleotides
GATA4 affinity-optimizing SNVs causal enhancer variants enhanceropathies enhancers heart development low affinity suboptimal affinity suboptimization

Journal

Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028

Informations de publication

Date de publication:
06 11 2023
Historique:
received: 20 12 2022
revised: 07 06 2023
accepted: 20 09 2023
medline: 9 11 2023
pubmed: 18 10 2023
entrez: 17 10 2023
Statut: ppublish

Résumé

Transcriptional enhancers direct precise gene expression patterns during development and harbor the majority of variants associated with phenotypic diversity, evolutionary adaptations, and disease. Pinpointing which enhancer variants contribute to changes in gene expression and phenotypes is a major challenge. Here, we find that suboptimal or low-affinity binding sites are necessary for precise gene expression during heart development. Single-nucleotide variants (SNVs) can optimize the affinity of ETS binding sites, causing gain-of-function (GOF) gene expression, cell migration defects, and phenotypes as severe as extra beating hearts in the marine chordate Ciona robusta. In human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, a SNV within a human GATA4 enhancer increases ETS binding affinity and causes GOF enhancer activity. The prevalence of suboptimal-affinity sites within enhancers creates a vulnerability whereby affinity-optimizing SNVs can lead to GOF gene expression, changes in cellular identity, and organismal-level phenotypes that could contribute to the evolution of novel traits or diseases.

Identifiants

DOI: 10.1016/j.devcel.2023.09.005 PMID: 37848026
pubmed: 37848026
pii: S1534-5807(23)00492-6
doi: 10.1016/j.devcel.2023.09.005
pii:
doi:

Substances chimiques

Nucleotides 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

2206-2216.e5

Subventions

Organisme : NIGMS NIH HHS
ID : T32 GM133351
Pays : United States
Organisme : NHGRI NIH HHS
ID : DP2 HG010013
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA051234
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL107442
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007444
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008666
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH113715
Pays : United States
Organisme : NIDA NIH HHS
ID : P50 DA037844
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM127235
Pays : United States
Organisme : NIH HHS
ID : S10 OD026929
Pays : United States

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Granton A Jindal (GA)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

Alexis T Bantle (AT)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.

Joe J Solvason (JJ)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.

Jessica L Grudzien (JL)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

Agnieszka D'Antonio-Chronowska (A)

Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

Fabian Lim (F)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.

Sophia H Le (SH)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

Benjamin P Song (BP)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.

Michelle F Ragsac (MF)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.

Adam Klie (A)

Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.

Reid O Larsen (RO)

Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.

Kelly A Frazer (KA)

Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

Emma K Farley (EK)

Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: efarley@ucsd.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Single-nucleotide variants within heart...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Éléments activateurs (génétique) › Single-nucleotide variants within heart...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › Single-nucleotide variants within heart...
questionsmedicales.fr › Cellules › Cellules musculaires › Myocytes cardiaques › Single-nucleotide variants within heart...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Single-nucleotide variants within heart...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Single-nucleotide variants within heart...