A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network.

RNA RNA, long noncoding RNA, untranslated atrial fibrillation calcium signaling gene regulatory networks heart failure

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
08 Jan 2024
Historique:
medline: 8 1 2024
pubmed: 8 1 2024
entrez: 8 1 2024
Statut: aheadofprint

Résumé

The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF. The pathophysiological basis of AF in the context of HF is presumed to result from atrial remodeling. Upregulation of the transcription factor FOG2 (friend of GATA2; encoded by FOG2 expression was assessed in human atria. The effect of adult-specific FOG2 overexpression in the mouse heart was evaluated by whole animal electrophysiology, in vivo organ electrophysiology, cellular electrophysiology, calcium flux, mouse genetic interactions, gene expression, and genomic function, including a novel approach for defining functional transcription factor interactions based on overlapping effects on enhancer noncoding transcription. FOG2 is significantly upregulated in the human atria during HF. Adult cardiomyocyte-specific FOG2 overexpression in mice caused primary spontaneous AF before the development of HF or atrial remodeling. FOG2 overexpression generated arrhythmia substrate and trigger in cardiomyocytes, including calcium cycling defects. We found that FOG2 repressed atrial gene expression promoted by Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network, providing a genomic link between HF and AF risk independent of atrial remodeling.

Sections du résumé

BACKGROUND UNASSIGNED
The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF. The pathophysiological basis of AF in the context of HF is presumed to result from atrial remodeling. Upregulation of the transcription factor FOG2 (friend of GATA2; encoded by
METHODS UNASSIGNED
FOG2 expression was assessed in human atria. The effect of adult-specific FOG2 overexpression in the mouse heart was evaluated by whole animal electrophysiology, in vivo organ electrophysiology, cellular electrophysiology, calcium flux, mouse genetic interactions, gene expression, and genomic function, including a novel approach for defining functional transcription factor interactions based on overlapping effects on enhancer noncoding transcription.
RESULTS UNASSIGNED
FOG2 is significantly upregulated in the human atria during HF. Adult cardiomyocyte-specific FOG2 overexpression in mice caused primary spontaneous AF before the development of HF or atrial remodeling. FOG2 overexpression generated arrhythmia substrate and trigger in cardiomyocytes, including calcium cycling defects. We found that FOG2 repressed atrial gene expression promoted by
CONCLUSIONS UNASSIGNED
Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network, providing a genomic link between HF and AF risk independent of atrial remodeling.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.123.066804 PMID: 38189150
pubmed: 38189150
doi: 10.1161/CIRCULATIONAHA.123.066804
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Auteurs

Michael T Broman (MT)

Department of Medicine, Section of Cardiology, University of Chicago, IL. (M.T.B., B.L., S.R.M.).

Rangarajan D Nadadur (RD)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).

Carlos Perez-Cervantes (C)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
ORCID: 0000-0003-1352-7322

Ozanna Burnicka-Turek (O)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
ORCID: 0000-0002-3770-4314

Sonja Lazarevic (S)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).

Anna Gams (A)

Department of Biomedical Engineering, George Washington University, Washington, DC. (A.G., I.R.E.).
ORCID: 0000-0002-3052-8469

Brigitte Laforest (B)

Department of Medicine, Section of Cardiology, University of Chicago, IL. (M.T.B., B.L., S.R.M.).

Jeffrey D Steimle (JD)

Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).

Sabrina Iddir (S)

Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).

Zhezhen Wang (Z)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).

Linsin Smith (L)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).

Stefan R Mazurek (SR)

Department of Medicine, Section of Cardiology, University of Chicago, IL. (M.T.B., B.L., S.R.M.).

Harold E Olivey (HE)

Department of Biology, Indiana University Northwest, Gary (H.E.O.).

Pingzhu Zhou (P)

School of Medicine, Shanghai University, China (P.Z.).
ORCID: 0000-0002-1917-257X

Margaret Gadek (M)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
ORCID: 0000-0001-5453-6909

Kaitlyn M Shen (KM)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
ORCID: 0000-0002-9085-6384

Zoheb Khan (Z)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).

Joshua W M Theisen (JWM)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
ORCID: 0000-0002-6267-5391

Xinan H Yang (XH)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
ORCID: 0000-0001-8061-8692

Kohta Ikegami (K)

Division of Molecular and Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, OH (K.I.).
ORCID: 0000-0002-0405-1193

Igor R Efimov (IR)

Department of Biomedical Engineering, George Washington University, Washington, DC. (A.G., I.R.E.).
ORCID: 0000-0002-1483-5039

William T Pu (WT)

Harvard Stem Cell Institute, Harvard University, Cambridge, MA (W.T.P.).
Department of Cardiology, Boston Children's Hospital, MA (W.T.P.).
ORCID: 0000-0002-4551-8079

Christopher R Weber (CR)

Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
ORCID: 0000-0002-2117-3184

Elizabeth M McNally (EM)

Center for Genetic Medicine, Northwestern University, Chicago, IL (E.M.M.).
ORCID: 0000-0002-1221-719X

Eric C Svensson (EC)

Boston Pharmaceuticals, Cambridge, MA (E.C.S.).

Ivan P Moskowitz (IP)

Departments of Pediatrics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
Pathology, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., C.R.W., I.P.M.).
Human Genetics, University of Chicago, IL. (R.D.N., C.P.-C., O.B.-T., S.L., J.D.S., S.I., Z.W., L.S., M.G., K.M.S., Z.K., J.W.M.T., X.H.Y., I.P.M.).
ORCID: 0000-0003-0014-4963

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