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SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state.

Ruben Sebastian-Perez | Shoma Nakagawa | Xiaochuan Tu | Sergi Aranda | Martina Pesaresi | Pablo Aurelio Gomez-Garcia | Marc Alcoverro-Bertran | Jose Luis Gomez-Vazquez | Davide Carnevali | Eva Borràs | Eduard Sabidó | Laura Martin | Malka Nissim-Rafinia | Eran Meshorer | Maria Victoria Neguembor | Luciano Di Croce | Maria Pia Cosma
eLife | 2025

Chromocenters are established after the 2-cell (2C) stage during mouse embryonic development, but the factors that mediate chromocenter formation remain largely unknown. To identify regulators of 2C heterochromatin establishment in mice, we generated an inducible system to convert embryonic stem cells (ESCs) to 2C-like cells. This conversion is marked by a global reorganization and dispersion of H3K9me3-heterochromatin foci, which are then reversibly formed upon re-entry into pluripotency. By profiling the chromatin-bound proteome (chromatome) through genome capture of ESCs transitioning to 2C-like cells, we uncover chromatin regulators involved in de novo heterochromatin formation. We identified TOPBP1 and investigated its binding partner SMARCAD1. SMARCAD1 and TOPBP1 associate with H3K9me3-heterochromatin in ESCs. Interestingly, the nuclear localization of SMARCAD1 is lost in 2C-like cells. SMARCAD1 or TOPBP1 depletion in mouse embryos leads to developmental arrest, reduction of H3K9me3, and remodeling of heterochromatin foci. Collectively, our findings contribute to comprehending the maintenance of chromocenters during early development.

Pubmed ID: 39969508

Associated grants

  • Agency: Horizon 2020 Framework Programme,
    Id: 686637
  • Agency: Horizon 2020 Framework Programme,
    Id: 964342
  • Agency: Ministerio de Ciencia e Innovación,
    Id: PID2020-114080GB I00/AEI/10.13039/501100011033
  • Agency: Ministerio de Ciencia e Innovación,
    Id: BFU2017-86760-P/AEI/FEDER
  • Agency: Agència de Gestió d'Ajuts Universitaris i de Recerca,
    Id: 2021-SGR2021-01300
  • Agency: Fundació la Marató de TV3,
    Id: 202027-10
  • Agency: National Natural Science Foundation of China,
    Id: 31971177
  • Agency: Ministerio de Economía y Competitividad,
    Id: PID2019-108322GB-100
  • Agency: Instituto de Salud Carlos III,
    Id: PT17/0019
  • Agency: Departament d'Empresa i Coneixement, Generalitat de Catalunya,
    Id: 2018FI_B_00637
  • Agency: Ministerio de Ciencia e Innovación,
    Id: PRE2018-085107
  • Agency: Ministerio de Ciencia, Innovación y Universidades,
    Id: RYC-2018-025002-I
  • Agency: Instituto de Salud Carlos III,
    Id: PI19/01814
  • Agency: Ministerio de Ciencia e Innovación,
    Id: 2014ES05SFOP007
  • Agency: 'la Caixa' Foundation,
    Id: LCF/BQ/DR20/11790016
  • Agency: Ministerio de Economía y Competitividad,
    Id: BES-2015-072802
  • Agency: FP7 People: Marie-Curie Actions,
    Id: 608959
  • Agency: Ministerio de Ciencia e Innovación,
    Id: Juan de la Cierva-Incorporación 2017

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