Deficiency of CXXC finger protein 1 leads to small changes in heart rate but moderate epigenetic alterations and significant protein downregulation of hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) ion channels in mice

被引:5
作者
Shi, Ling [1 ]
Shen, Jingling [2 ,3 ]
Jin, Xuexin [1 ]
Li, Zheng [1 ]
Ma, Jiudong [1 ]
Huang, Xiang [1 ]
Guo, Yang [1 ]
Ma, Wenbo [1 ]
Gong, Dongmei [1 ]
Yang, Baofeng [1 ]
Pan, Zhenwei [1 ,4 ]
机构
[1] Harbin Med Univ, Coll Pharm, Minist Educ, Dept Pharmacol,Key Lab Cardiovasc Res, Harbin, Peoples R China
[2] Wenzhou Univ, Inst Life Sci, Wenzhou, Peoples R China
[3] Wenzhou Univ, Coll Life & Environm Sci, Wenzhou, Peoples R China
[4] Harbin Med Univ, Affiliated Hosp 1, Key Lab Cell Transplantat, Harbin, Peoples R China
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
CXXC finger protein 1; Epigenetic modification; Hyper-polarization-activated cyclic nucleotide-gated 4 (HCN4); I-f current; Sinus bradycardia; SINOATRIAL; METHYLATION; EXPRESSION; CONDUCTION; MYOCYTES; CELLS;
D O I
10.1016/j.hrthm.2021.06.1190
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND The normal cardiac rhythm is generated in the sino-atrial node (SAN). Changes in ionic currents of the SAN may cause sinus arrhythmia. CXXC finger protein 1 (Cfp1) is an epigenetic regulator that is involved in transcriptional regulation of multiple genes. OBJECTIVE The purpose of this study was to explore whether Cfp1 controls SAN function through regulation of ion channel-related genes. METHODS Electrophysiological study, patch clamp recording, reverse transcriptase polymerase chain reaction, optical mapping, chromatin immunoprecipitation, and immunofluorescence staining were performed to evaluate the function of SAN and underlying mechanism on Cfp1 heterozygous knockout (Cfp1(+/-)) mice. RESULTS Heart rate was slower slightly and SAN recovery time was longer in Cfp1(+/-) mice than controls. Whole-cell patch-clamp recording showed that the firing rate of action potentials was reduced in Cfp1(+/-) mice. The density of If current was reduced by 66% in SAN cells of Cfp1(+/-) mice but the densities of ICa, ICa-L, and ICa-T were not changed. The hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) mRNA level in SAN tissue of Cfp1(+/-) mice was reduced. The HCN4 protein was significantly decreased in SAN cells and tissues after heterozygous deletion of Cfp1. Chro-matin immunoprecipitation assay on cultured HL-1 cells demonstrated that Cfp1 was enriched in the promoter regions of HCN4. Knockdown of Cfp1 reduced H3K4 trimethylation, H3K9 acetylation, and H3K27 acetylation of HCN4 promoter region. CONCLUSION Deficiency of Cfp1 leads to small changes in heart rate by moderate epigenetic modification alterations and significant protein downregulation of HCN4 ion channels in mice.
引用
收藏
页码:1780 / 1789
页数:10
相关论文
共 28 条
[1]  
Alig J, 2009, P NATL ACAD SCI USA, V106, P12189, DOI 10.1073/pnas.0810332106
[2]   ATP-sensitive potassium channels in the sinoatrial node contribute to heart rate control and adaptation to hypoxia [J].
Aziz, Qadeer ;
Finlay, Malcolm ;
Montaigne, David ;
Ojake, Leona ;
Li, Yiwen ;
Anderson, Naomi ;
Ludwig, Andreas ;
Tinker, Andrew .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2018, 293 (23) :8912-8921
[3]   Distribution of the pacemaker HCN4 channel mRNA and protein in the rabbit sinoatrial node [J].
Brioschi, Chiara ;
Micheloni, Stefano ;
Tellez, James O. ;
Pisoni, Giuliano ;
Longhi, Renato ;
Moroni, Paolo ;
Billeter, Rudi ;
Barbuti, Andrea ;
Dobrzynski, Halina ;
Boyett, Mark R. ;
DiFrancesco, Dario ;
Baruscotti, Mirko .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2009, 47 (02) :221-227
[4]   Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current [J].
Bucchi, Annalisa ;
BaruSCotti, Mad ;
Robinson, Richard B. ;
DiFrancesco, Dario .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2007, 43 (01) :39-48
[5]   Cfp1 is required for gene expression-dependent H3K4 trimethylation and H3K9 acetylation in embryonic stem cells [J].
Clouaire, Thomas ;
Webb, Shaun ;
Bird, Adrian .
GENOME BIOLOGY, 2014, 15 (09) :451
[6]   Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues [J].
Dobrzynski, Halina ;
Anderson, Robert H. ;
Atkinson, Andrew ;
Borbas, Zoltan ;
D'Souza, Alicia ;
Fraser, John F. ;
Inada, Shin ;
Logantha, Sunil J. R. J. ;
Monfredi, Oliver ;
Morris, Gwilym M. ;
Moorman, Anton F. M. ;
Nikolaidou, Thodora ;
Schneider, Heiko ;
Szuts, Viktoria ;
Temple, Ian P. ;
Yanni, Joseph ;
Boyett, Mark R. .
PHARMACOLOGY & THERAPEUTICS, 2013, 139 (02) :260-288
[7]   YY1 Expression Is Sufficient for the Maintenance of Cardiac Progenitor Cell State [J].
Gregoire, Serge ;
Li, Guang ;
Sturzu, Anthony C. ;
Schwartz, Robert J. ;
Wu, Sean M. .
STEM CELLS, 2017, 35 (08) :1913-1923
[8]   Cxxc Finger Protein 1 Positively Regulates GM-CSF-Derived Macrophage Phagocytosis Through Csf2rα-Mediated Signaling [J].
Hui, Zhaoyuan ;
Zhou, Lina ;
Xue, Zhonghui ;
Zhou, Lingfeng ;
Luo, Yikai ;
Lin, Feng ;
Liu, Xia ;
Hong, Shenghui ;
Li, Wei ;
Wang, Di ;
Lu, Linrong ;
Wang, Jianli ;
Wang, Lie .
FRONTIERS IN IMMUNOLOGY, 2018, 9
[9]   Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents [J].
Khandekar, Aditi ;
Springer, Steven ;
Wang, Wei ;
Hicks, Stephanie ;
Weinheimer, Carla ;
Diaz-Trelles, Ramon ;
Nerbonne, Jeanne M. ;
Rentschler, Stacey .
CIRCULATION RESEARCH, 2016, 119 (12) :1324-1338
[10]   Ionic mechanisms of the action of anaesthetics on sinoatrial node automaticity [J].
Kojima, Akiko ;
Matsuura, Hiroshi .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2017, 814 :63-72