Loss of the Atrial Fibrillation-Related Gene, Zfhx3, Results in Atrial Dilation and Arrhythmias

Jameson，Heather S.1; Hanley，Alan1,2; Hill，Matthew C.1,3; Xiao，Ling1; Ye，Jiangchuan1,3; Bapat，Aneesh1,2; Ronzier，Elsa1; Hall，Amelia Weber1,3; Hucker，William J.1,2; Clauss，Sebastian1,4,5,6,7; Barazza，Miranda1; Silber，Elizabeth1; Mina，Julie A.1; Tucker，Nathan R.8; Mills，Robert W.1; Dong，Jin Tang9; Milan，David J.10; Ellinor，Patrick T.1,2,3

2023-08-04

10.1161/CIRCRESAHA.123.323029

Circulation Research   Impact Factor & Quartile

0009-7330

1524-4571

Background: ZFHX3 (zinc finger homeobox 3), a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, magnetic resonance imaging, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 loss (Zfhx3 Het and knockout, respectively). Human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. Results: We found single-nucleotide polymorphism (SNP) rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than Zfhx3 Het and wild-type mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. Conclusions: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.

atrial fibrillation electrophysiology mice myocytes, cardiac transcription factors

SCI

English

Others

National Institutes of Health (NIH)["1RO1H L092577","1R01H L157635","5R01H L139731"] ; American Heart Association Strategically Focused Research Networks[18SFRN34110082] ; European Union (Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation (MAESTRIA))[965286] ; NIH[5T32H L0072084] ; American Heart Association Career Development Award[20CDA35260081] ; NIH Mentored Research Scientist Career Development Award[7K01HL140187] ; Marie Curie International Outgoing Fellowship within the Seventh European Community Framework Program[PIOF-GA-2012-328352] ; German Center for Cardiovascular Research (Deutsches Zentrum fur Herz-Kreislauf-Forschung (DZHK))["81X2600210","81X2600204"]

Cardiovascular System & Cardiology ; Hematology

Cardiac & Cardiovascular Systems ; Hematology ; Peripheral Vascular Disease

WOS:001041566200002

LIPPINCOTT WILLIAMS & WILKINS

CLINICAL MEDICINE

2-s2.0-85166479095

Scopus

1.Cardiovascular Research Center,Massachusetts General Hospital,Boston,United States
2.Demoulas Center for Cardiac Arrhythmias,Massachusetts General Hospital,Boston,United States
3.Cardiovascular Disease Initiative,The Broad Institute of MIT and Harvard,Cambridge,United States
4.University Hospital Munich,Ludwig-Maximilians University (LMU),Department of Medicine I,Campus Grosshadern,Munich,Marchioninistrasse 15,D-81377,Germany
5.German Centre for Cardiovascular Research (DZHK),Partner Site: Munich Heart Alliance,Munich,Germany
6.Institute of Surgical Research,The Walter-Brendel-Centre of Experimental Medicine,University Hospital,LMU Munich,Munich,Marchioninistrasse 27,D-81377,Germany
7.Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer,LMU Munich,Munich,D-81377,Germany
8.Masonic Medical Research Institute,Utica,United States
9.Department of Human Cell Biology and Genetics,Southern University of Science and Technology,School of Medicine,Shenzhen,China
10.Leducq Foundation,Boston,United States

Jameson，Heather S.,Hanley，Alan,Hill，Matthew C.,et al. Loss of the Atrial Fibrillation-Related Gene, Zfhx3, Results in Atrial Dilation and Arrhythmias[J]. Circulation Research,2023,133(4):313-329.

Jameson，Heather S..,Hanley，Alan.,Hill，Matthew C..,Xiao，Ling.,Ye，Jiangchuan.,...&Ellinor，Patrick T..(2023).Loss of the Atrial Fibrillation-Related Gene, Zfhx3, Results in Atrial Dilation and Arrhythmias.Circulation Research,133(4),313-329.

Jameson，Heather S.,et al."Loss of the Atrial Fibrillation-Related Gene, Zfhx3, Results in Atrial Dilation and Arrhythmias".Circulation Research 133.4(2023):313-329.