Transcription factor protein interactomes reveal genetic determinants in heart disease

Barbara Gonzalez-Teran; Maureen Pittman; Franco Felix; Reuben Thomas; Desmond Richmond-Buccola; Ruth Hüttenhain; Krishna Choudhary; Elisabetta Moroni; Mauro W Costa; Yu Huang; Arun Padmanabhan; Michael Alexanian; Clara Youngna Lee; Bonnie E J Maven; Kaitlen Samse-Knapp; Sarah U Morton; Michael McGregor; Casey A Gifford; J G Seidman; Christine E Seidman; Bruce D Gelb; Giorgio Colombo; Bruce R Conklin; Brian L Black; Benoit G Bruneau; Nevan J Krogan; Katherine S Pollard; Deepak Srivastava

doi:10.1016/j.cell.2022.01.021

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. Epub 2022 Feb 18.

Authors

Barbara Gonzalez-Teran¹, Maureen Pittman², Franco Felix¹, Reuben Thomas³, Desmond Richmond-Buccola¹, Ruth Hüttenhain⁴, Krishna Choudhary³, Elisabetta Moroni⁵, Mauro W Costa¹, Yu Huang¹, Arun Padmanabhan⁶, Michael Alexanian¹, Clara Youngna Lee¹, Bonnie E J Maven⁷, Kaitlen Samse-Knapp¹, Sarah U Morton⁸, Michael McGregor⁴, Casey A Gifford¹, J G Seidman⁹, Christine E Seidman¹⁰, Bruce D Gelb¹¹, Giorgio Colombo¹², Bruce R Conklin¹, Brian L Black¹³, Benoit G Bruneau¹⁴, Nevan J Krogan⁴, Katherine S Pollard¹⁵, Deepak Srivastava¹⁶

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.

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.

MeSH terms

Animals
GATA4 Transcription Factor / metabolism*
Heart Defects, Congenital* / genetics
Mice
Mutation
Nuclear Proteins / metabolism*
Oxidoreductases / metabolism*
Proteomics
T-Box Domain Proteins / genetics
Transcription Factors* / genetics

Substances

GATA4 Transcription Factor
Gata4 protein, mouse
Nuclear Proteins
T-Box Domain Proteins
Transcription Factors
Glyr1 protein, mouse
Oxidoreductases

Abstract

MeSH terms

Substances

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