Recruitment of homodimeric proneural factors by conserved CAT-CAT E-boxes drives major epigenetic reconfiguration in cortical neurogenesis

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  • dc.contributor.author de Martin, Xabier
  • dc.contributor.author Oliva Miguel, Baldomero
  • dc.contributor.author Santpere Baró, Gabriel, 1981-
  • dc.date.accessioned 2025-02-05T07:08:55Z
  • dc.date.available 2025-02-05T07:08:55Z
  • dc.date.issued 2024
  • dc.description.abstract Proneural factors of the basic helix-loop-helix family coordinate neurogenesis and neurodifferentiation. Among them, NEUROG2 and NEUROD2 subsequently act to specify neurons of the glutamatergic lineage. Disruption of these factors, their target genes and binding DNA motifs has been linked to various neuropsychiatric disorders. Proneural factors bind to specific DNA motifs called E-boxes (hexanucleotides of the form CANNTG, composed of two CAN half sites on opposed strands). While corticogenesis heavily relies on E-box activity, the collaboration of proneural factors on different E-box types and their chromatin remodeling mechanisms remain largely unknown. Here, we conducted a comprehensive analysis using chromatin immunoprecipitation followed by sequencing (ChIP-seq) data for NEUROG2 and NEUROD2, along with time-matched single-cell RNA-seq, ATAC-seq and DNA methylation data from the developing mouse cortex. Our findings show that these factors are highly enriched in transiently active genomic regions during intermediate stages of neuronal differentiation. Although they primarily bind CAG-containing E-boxes, their binding in dynamic regions is notably enriched in CAT-CAT E-boxes (i.e. CATATG, denoted as 5'3' half sites for dimers), which undergo significant DNA demethylation and exhibit the highest levels of evolutionary constraint. Aided by HT-SELEX data reanalysis, structural modeling and DNA footprinting, we propose that these proneural factors exert maximal chromatin remodeling influence during intermediate stages of neurogenesis by binding as homodimers to CAT-CAT motifs. This study provides an in-depth integrative analysis of the dynamic regulation of E-boxes during neuronal development, enhancing our understanding of the mechanisms underlying the binding specificity of critical proneural factors.
  • dc.description.sponsorship Agencia Estatal de Investigación /AEI/10.13039/501100011033 [PID2020-113203RB-I00 to B.O., PID2019-104700GA-I00 and PID2022-140137NB-I00 to G.S.]; Instituto de Salud Carlos III [CP20/00064], with co-financing by European Funds for the Miguel Servet Contract; Fundació la Marató de TV3; NIH [R01HG010898-01 to G.S]; Unidad de Excelencia María de Maeztu [CEX2018-000792-M]; MCIN [PRE2020-093064 to X.d.M.]. Funding for open access charge: Instituto de Salud Carlos III [CP20/00064], with co-financing by European Funds for the Miguel Servet Contract.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation de Martin X, Oliva B, Santpere G. Recruitment of homodimeric proneural factors by conserved CAT-CAT E-boxes drives major epigenetic reconfiguration in cortical neurogenesis. Nucleic Acids Res. 2024 Nov 27;52(21):12895-917. DOI: 10.1093/nar/gkae950
  • dc.identifier.doi http://dx.doi.org/10.1093/nar/gkae950
  • dc.identifier.issn 0305-1048
  • dc.identifier.uri http://hdl.handle.net/10230/69489
  • dc.language.iso eng
  • dc.publisher Oxford University Press
  • dc.relation.ispartof Nucleic Acids Res. 2024 Nov 27;52(21):12895-917
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-113203RB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104700GA-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-140137NB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000792-M
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PRE2020-093064
  • dc.rights © The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Gene regulation
  • dc.subject.keyword Chromatin and epigenetics
  • dc.title Recruitment of homodimeric proneural factors by conserved CAT-CAT E-boxes drives major epigenetic reconfiguration in cortical neurogenesis
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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