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Rebalancing gene haploinsufficiency in vivo by targeting chromatin

Author

Listed:
  • Filomena Gabriella Fulcoli

    (CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso)

  • Monica Franzese

    (Istituto per le Applicazioni del Calcolo, CNR)

  • Xiangyang Liu

    (Shanghai Pediatric Congenital Heart Institute, Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine)

  • Zhen Zhang

    (Shanghai Pediatric Congenital Heart Institute, Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine)

  • Claudia Angelini

    (Istituto per le Applicazioni del Calcolo, CNR)

  • Antonio Baldini

    (CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
    University of Naples Federico II)

Abstract

Congenital heart disease (CHD) affects eight out of 1,000 live births and is a major social and health-care burden. A common genetic cause of CHD is the 22q11.2 deletion, which is the basis of the homonymous deletion syndrome (22q11.2DS), also known as DiGeorge syndrome. Most of its clinical spectrum is caused by haploinsufficiency of Tbx1, a gene encoding a T-box transcription factor. Here we show that Tbx1 positively regulates monomethylation of histone 3 lysine 4 (H3K4me1) through interaction with and recruitment of histone methyltransferases. Treatment of cells with tranylcypromine (TCP), an inhibitor of histone demethylases, rebalances the loss of H3K4me1 and rescues the expression of approximately one-third of the genes dysregulated by Tbx1 suppression. In Tbx1 mouse mutants, TCP treatment ameliorates substantially the cardiovascular phenotype. These data suggest that epigenetic drugs may represent a potential therapeutic strategy for rescue of gene haploinsufficiency phenotypes, including structural defects.

Suggested Citation

  • Filomena Gabriella Fulcoli & Monica Franzese & Xiangyang Liu & Zhen Zhang & Claudia Angelini & Antonio Baldini, 2016. "Rebalancing gene haploinsufficiency in vivo by targeting chromatin," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11688
    DOI: 10.1038/ncomms11688
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    Cited by:

    1. Tae-Yeon Eom & J. Eric Schmitt & Yiran Li & Christopher M. Davenport & Jeffrey Steinberg & Audrey Bonnan & Shahinur Alam & Young Sang Ryu & Leena Paul & Baranda S. Hansen & Khaled Khairy & Stephane Pe, 2024. "Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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