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Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function

Author

Listed:
  • Yinuo Wang

    (Heidelberg University
    German Centre for Cardiovascular Research (DZHK))

  • Adel Elsherbiny

    (Heidelberg University)

  • Linda Kessler

    (Heidelberg University)

  • Julio Cordero

    (Heidelberg University
    German Centre for Cardiovascular Research (DZHK))

  • Haojie Shi

    (Heidelberg University
    German Centre for Cardiovascular Research (DZHK))

  • Heike Serke

    (Heidelberg University
    German Centre for Cardiovascular Research (DZHK))

  • Olga Lityagina

    (Heidelberg University)

  • Felix A. Trogisch

    (German Centre for Cardiovascular Research (DZHK)
    Heidelberg University)

  • Mona Malek Mohammadi

    (German Centre for Cardiovascular Research (DZHK)
    Heidelberg University
    Medical Faculty University of Bonn)

  • Ibrahim El-Battrawy

    (University Medical Centre Mannheim (UMM), Heidelberg University
    Ruhr University)

  • Johannes Backs

    (German Centre for Cardiovascular Research (DZHK)
    Heidelberg University)

  • Thomas Wieland

    (German Centre for Cardiovascular Research (DZHK)
    Heidelberg University)

  • Joerg Heineke

    (German Centre for Cardiovascular Research (DZHK)
    Heidelberg University)

  • Gergana Dobreva

    (Heidelberg University
    German Centre for Cardiovascular Research (DZHK))

Abstract

Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We report changes in chromatin compaction and localization of cardiac genes in Lmna−/− ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate. This is accompanied by premature cardiomyocyte differentiation, cell cycle withdrawal and abnormal contractility. Gata4 is activated by lamin A/C loss and Gata4 silencing or haploinsufficiency rescues the aberrant cardiovascular cell fate choices induced by lamin A/C deficiency. We uncover divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which have distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. We conclude that disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy.

Suggested Citation

  • Yinuo Wang & Adel Elsherbiny & Linda Kessler & Julio Cordero & Haojie Shi & Heike Serke & Olga Lityagina & Felix A. Trogisch & Mona Malek Mohammadi & Ibrahim El-Battrawy & Johannes Backs & Thomas Wiel, 2022. "Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34366-7
    DOI: 10.1038/s41467-022-34366-7
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