Zfhx3 Transcription Factor Represses the Expression of SCN5A Gene and Decreases Sodium Current Density (INa)

Rubio-Alarcón, Marcos; Cámara-Checa, Anabel; Dago, María; Crespo-García, Teresa; Nieto-Marín, Paloma; Marín, María; Merino, José Luís; Toquero, Jorge; Salguero‐Bodes, Rafael; Tamargo, Juan; Cebrián, Jorge; Delpón, Eva; Caballero, Ricardo

doi:10.3390/ijms222313031

Cited by 11 publications

(7 citation statements)

References 38 publications

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“…These results are consistent with previous studies evaluating the repressive role of Zfhx3 on other cardiac-specific transcription factors, including Tbx5 (Figure 6G). 32…”

Section: Resultsmentioning

confidence: 99%

“…40 Further, genes associated with cardiac muscle contraction and protein translation were also significantly downregulated. 32,36,41 Human single-nucleus ATAC-sequencing data, revealed atrial target genes regulated directly by ZFHX3 in cardiomyocytes, and these genes were involved in molecular pathways related to cardiac development, VEGF signaling, Wnt signaling, calcium binding, and heart contraction. These findings are consistent with the impaired calcium handling observed in Zfhx3 knockout mice, and further implicate ZFHX3 as a regulator of cardiac conduction.…”

Section: Discussionmentioning

confidence: 99%

“…These results are consistent with previous studies evaluating the repressive role of Zfhx3 on other cardiac-specific transcription factors, including Tbx5 (Figure 6G). 32 Zfhx3 Loss Ultimately Leads to the Development of a Dilated Cardiomyopathy, Atrial Enlargement, and Intraatrial Thrombus Formation…”

Section: Zfhx3 Directly Regulates Genes Related To Cardiac Conduction...mentioning

confidence: 99%

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

Jameson,

Hanley,

Hill

et al. 2023

Circulation Research

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Background: ZFHX3 , 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 deletion ( Zfhx3 Het and knockout, respectively). Human cardiac single-nucleus ATAC-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3 . Results: We found 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.

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“…These results are consistent with previous studies evaluating the repressive role of Zfhx3 on other cardiac-specific transcription factors, including Tbx5 (Figure 6G). 32…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Zfhx3 Directly Regulates Genes Related To Cardiac Conduction...mentioning

confidence: 99%

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

Jameson,

Hanley,

Hill

et al. 2023

Circulation Research

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“…ATBF1 is the largest transcription factor known to date and plays essential functions in both physiological and pathological processes. Mutations, deletions and single nucleotide polymorphisms (SNPs) of ATBF1 were correlated with multiple diseases, including cancers [ 5 , 9 , 10 , 22 , 29 ] and cardiovascular diseases [ 30 , 31 ]. ATBF1 has been demonstrated to be a potential diagnostic marker for skin cancer, prostate cancer, gastric cancer, bladder cancer and non-small cell lung cancer (NSCLC) [ 9 , 12 , 13 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

ATBF1 is a potential diagnostic marker of histological grade and functions via WNT5A in breast cancer

Zheng

et al. 2022

BMC Cancer

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Background Histological grade has been demonstrated to be an important factor of breast cancer outcome and is associated with cell differentiation and is currently being evaluated via H&E-stained sections. Molecular biomarkers are essential to improve the accuracy of histological grading. ATBF1, a large transcription factor, has been considered a tumor suppressor gene with frequent mutations or deletions in multiple cancers. In breast cancer, ATBF1 was reported to function in cell differentiation and mammary development. However, its role in the clinic has rarely been reported. Methods Breast cancer tissues (BCTs) and adjacent noncancerous tissues (ANCTs) were collected to analyze the expression of ATBF1 at the mRNA and protein levels. Three anti-ATBF1 antibodies recognizing independent peptides of ATBF1 (N-terminal end, middle region and C-terminal end) were applied for IHC staining. Small interfering RNA (siRNA) was used to silence ATBF1 expression and to investigate the roles of ATBF1 in MCF7 cells. Microarrays were introduced to analyze the differentially expressed genes, enriched GO terms and KEGG terms regulated by ATBF1 and its potential downstream genes, which were further confirmed in vitro and in clinical samples. Results The expression of ATBF1 was reduced in BCTs at both the mRNA and protein levels compared with that in ANCTs. ATBF1 protein was predominantly localized in the nucleus of ANCTs but in the cytoplasm of BCTs. Both the mRNA and protein levels of ATBF1 were significantly correlated with histological grade. Consistently, knockdown of ATBF1 increased stemness marker expression and reduced differentiation markers in vitro. Further analysis identified WNT5A as an essential downstream gene of ATBF1 in breast cancer cells. Treatment of WNT5A disrupted cell proliferation induced by ATBF1 silencing. In BCTs, a significant correlation was observed between the expression of WNT5A and ATBF1. Conclusion The results indicated that ATBF1 expression might be a useful diagnostic marker associated with histological grade and breast cancer malignancy. WNT5A and its signaling pathway are novel mechanisms by which ATBF1 contributes to breast cancer tumorigenesis.

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“…NM_010602 ; 96.41% homologous to human Kir6.2) subcloned in pECE was a generous gift from Dr. Colin Nichols (Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO; Borschel et al, 2017 ). The p.E322K Kir6.2 mutation was introduced using the QuikChange Site-Directed Mutagenesis kit (Agilent) and confirmed by direct DNA sequencing as previously described ( Tinaquero et al, 2020 ; Nieto-Marín et al, 2022 ; Rubio-Alarcón et al, 2021 ). The study has been conducted in Chinese hamster ovary (CHO) cells and human embryonic kidney 293 (HEK-293) cells purchased from American Type Culture Collection.…”

Section: Methodsmentioning

confidence: 99%

A Cantú syndrome mutation produces dual effects on KATP channels by disrupting ankyrin B regulation

Crespo-García

Rubio-Alarcón

Cámara-Checa

et al. 2022

Journal of General Physiology

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ATP-sensitive potassium (KATP) channels composed of Kir6.x and sulfonylurea receptor (SURs) subunits couple cellular metabolism to electrical activity. Cantú syndrome (CS) is a rare disease caused by mutations in the genes encoding Kir6.1 (KCNJ8) and SUR2A (ABCC9) that produce KATP channel hyperactivity due to a reduced channel block by physiological ATP concentrations. We functionally characterized the p.S1054Y SUR2A mutation identified in two CS carriers, who exhibited a mild phenotype although the mutation was predicted as highly pathogenic. We recorded macroscopic and single-channel currents in CHO and HEK-293 cells and measured the membrane expression of the channel subunits by biotinylation assays in HEK-293 cells. The mutation increased basal whole-cell current density and at the single-channel level, it augmented opening frequency, slope conductance, and open probability (Po), and promoted the appearance of multiple conductance levels. p.S1054Y also reduced Kir6.2 and SUR2A expression specifically at the membrane. Overexpression of ankyrin B (AnkB) prevented these gain- and loss-of-function effects, as well as the p.S1054Y-induced reduction of ATP inhibition of currents measured in inside-out macropatches. Yeast two-hybrid assays suggested that SUR2A WT and AnkB interact, while p.S1054Y interaction with AnkB is decreased. The p.E322K Kir6.2 mutation, which prevents AnkB binding to Kir6.2, produced similar biophysical alterations than p.S1054Y. Our results are the first demonstration of a CS mutation whose functional consequences involve the disruption of AnkB effects on KATP channels providing a novel mechanism by which CS mutations can reduce ATP block. Furthermore, they may help explain the mild phenotype associated with this mutation.

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Zfhx3 Transcription Factor Represses the Expression of SCN5A Gene and Decreases Sodium Current Density (INa)

Cited by 11 publications

References 38 publications

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

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

ATBF1 is a potential diagnostic marker of histological grade and functions via WNT5A in breast cancer

A Cantú syndrome mutation produces dual effects on KATP channels by disrupting ankyrin B regulation

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