2. Academic Validation
  3. Transcription factor protein interactomes reveal genetic determinants in heart disease

Transcription factor protein interactomes reveal genetic determinants in heart disease

  • Cell. 2022 Mar 3;185(5):794-814.e30. doi: 10.1016/j.cell.2022.01.021.
Barbara Gonzalez-Teran 1,  Maureen Pittman 2,  Franco Felix 1,  Reuben Thomas 3,  Desmond Richmond-Buccola 1,  Ruth Hüttenhain 4,  Krishna Choudhary 3,  Elisabetta Moroni 5,  Mauro W Costa 1,  Yu Huang 1,  Arun Padmanabhan 6,  Michael Alexanian 1,  Clara Youngna Lee 1,  Bonnie E J Maven 7,  Kaitlen Samse-Knapp 1,  Sarah U Morton 8,  Michael McGregor 4,  Casey A Gifford 1,  J G Seidman 9,  Christine E Seidman 10,  Bruce D Gelb 11,  Giorgio Colombo 12,  Bruce R Conklin 1,  Brian L Black 13,  Benoit G Bruneau 14,  Nevan J Krogan 4,  Katherine S Pollard 15,  Deepak Srivastava 16
Affiliations

Affiliations

  • 1 Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
  • 2 Gladstone Institutes, San Francisco, CA, USA; Department of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
  • 3 Gladstone Institutes, San Francisco, CA, USA.
  • 4 Gladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • 5 SCITEC-CNR, Milano, Italy.
  • 6 Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA; Division of Cardiology, Department of Medicine, University of California, San Francisco, CA, USA.
  • 7 Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA, USA.
  • 8 Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • 10 Department of Genetics, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA; Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
  • 11 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 12 University of Pavia, Department of Chemistry, Pavia, Italy.
  • 13 Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • 14 Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA; Division of Cardiology, Department of Pediatrics, UCSF School of Medicine, San Francisco, CA, USA.
  • 15 Gladstone Institutes, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; Department of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. Electronic address: katherine.pollard@gladstone.ucsf.edu.
  • 16 Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA; Division of Cardiology, Department of Pediatrics, UCSF School of Medicine, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA. Electronic address: deepak.srivastava@gladstone.ucsf.edu.
PMID: 35182466 DOI: 10.1016/j.cell.2022.01.021
Abstract

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.

Keywords

GATA4; GLYR1; NPAC; TBX5; congenital heart disease; de novo variants; disease variants; genetics; protein interactome networks.

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