Name	Ischemic heart disease
ICD	ICD-11: BA40-BA6Z

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[1]
Response Summary	Mettl14 resulted in enhanced levels of Wnt1 m6A modification and Wnt1 protein but not its transcript level.Furthermore, Mettl14 overexpression blocked I/R-induced downregulation of Wnt1 and Catenin beta-1 (CTNNB1/Beta-catenin) proteins, whereas Mettl14 hearts exhibited the opposite results. Mettl14 attenuates cardiac I/R injury by activating Wnt/Bete-catenin in an m6A-dependent manner, providing a novel therapeutic target for ischemic heart disease.
Responsed Disease	Ischemic heart disease [ICD-11: BA40-BA6Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Wnt signaling pathway			hsa04310
In-vitro Model	Neonatal rat ventricular cardiomyocytes (Primary myocyte cells)
In-vivo Model	C57BL/6 mouse hearts were subjected to ischemia/reperfusion (I/R) in vivo as described previously (Bock-Marquette et al., 2004; Song et al., 2015; Brocard et al., 2017). I/R injury in mice was induced by 45-min ischemia, followed by 7-day and 4-week reperfusion in a loss-of-function study (Figure 1) and gain-of-function study (Figure 2), respectively. In brief, mice were anesthetized with 2% avertin (0.1 ml/10g body weight; Sigma-Aldrich Corporation, United States) through intraperitoneal injection. To generate I/R injury, the left anterior descending coronary artery (LAD) was ligated with 7-0 nylon for 45 min and then was removed. For the sham group, a suture was passed under the LAD but without ligation. According to the experimental requirements, at different time points of cardiac I/R, the mice were anesthetized for assessing heart function by echocardiographic measurement. All the mice survived during the process of I/R injury after the operation.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[2]
Response Summary	METTL3 promoted DGCR8 binding to pri-miR-143-3p through m6A modification, thus enhancing miR-143-3p expression to inhibit Protein kinase C epsilon (PRKCE) transcription and further aggravating cardiomyocyte pyroptosis and MI/R injury.
Responsed Disease	Ischemic heart disease [ICD-11: BA40-BA6Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Down regulation
Cell Process	Pyroptosis
In-vitro Model	H9c2(2-1)	Normal	Rattus norvegicus	CVCL_0286
In-vivo Model	The thoracic cavity of rats was exposed, and the left anterior descending coronary artery was ligated with a 6-0 silk thread. Successfully surgical MI could be observed, with myocardium color fading and pulse weakening. After 30 min of ischemia, the blood flow was restored by releasing the slipknot, and then 120-min perfusion was performed. Afterward, the thoracic cavity of rats was sutured. The rats were assigned into 4 groups, with 12 rats in each group. Lentivirus packaged short hairpin (sh)-negative control (NC) and sh-METTL3 (GenePharma, Shanghai, China) were injected into the rats via tail vein 24 h before operation. The titer of lentivirus was 1?×?109 TU/mL, and the injection rate was 0.2 ul/min for 10 min. Blood samples were collected 24 h after reperfusion.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[1]
Response Summary	Mettl14 resulted in enhanced levels of Proto-oncogene Wnt-1 (Wnt1) m6A modification and Wnt1 protein but not its transcript level. Furthermore, Mettl14 overexpression blocked I/R-induced downregulation of Wnt1 and Bete-catenin proteins, whereas Mettl14 hearts exhibited the opposite results. Mettl14 attenuates cardiac I/R injury by activating Wnt/Bete-catenin in an m6A-dependent manner, providing a novel therapeutic target for ischemic heart disease.
Responsed Disease	Ischemic heart disease [ICD-11: BA40-BA6Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Wnt signaling pathway			hsa04310
In-vitro Model	Neonatal rat ventricular cardiomyocytes (Primary myocyte cells)
In-vivo Model	C57BL/6 mouse hearts were subjected to ischemia/reperfusion (I/R) in vivo as described previously (Bock-Marquette et al., 2004; Song et al., 2015; Brocard et al., 2017). I/R injury in mice was induced by 45-min ischemia, followed by 7-day and 4-week reperfusion in a loss-of-function study (Figure 1) and gain-of-function study (Figure 2), respectively. In brief, mice were anesthetized with 2% avertin (0.1 ml/10g body weight; Sigma-Aldrich Corporation, United States) through intraperitoneal injection. To generate I/R injury, the left anterior descending coronary artery (LAD) was ligated with 7-0 nylon for 45 min and then was removed. For the sham group, a suture was passed under the LAD but without ligation. According to the experimental requirements, at different time points of cardiac I/R, the mice were anesthetized for assessing heart function by echocardiographic measurement. All the mice survived during the process of I/R injury after the operation.

In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[3]
Response Summary	METTL3 methylates Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy genes, at two m6A residues in the 3'-UTR, which promotes the association of the RNA-binding protein HNRNPD with TFEB pre-mRNA and subsequently decreases the expression levels of TFEB. METTL3-ALKBH5 and autophagy, providing insight into the functional importance of the reversible mRNA m6A methylation and its modulators in ischemic heart disease.
Responsed Disease	Ischemic heart disease [ICD-11: BA40-BA6Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Down regulation
Pathway Response	Apoptosis			hsa04210)
Cell Process	Cell proliferation
In-vitro Model	H9c2(2-1)	Normal	Rattus norvegicus	CVCL_0286
	HEK293T	Normal	Homo sapiens	CVCL_0063
In-vivo Model	To cause I/R injury, mice were subjected to 30 min of LAD ischemia followed by 60 min of reperfusion.
Experiment 2 Reporting the m6A-centered Disease Response by This Target Gene				[3]
Response Summary	METTL3 methylates Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy genes, at two m6A residues in the 3'-UTR, which promotes the association of the RNA-binding protein HNRNPD with TFEB pre-mRNA and subsequently decreases the expression levels of TFEB. METTL3-ALKBH5 and autophagy, providing insight into the functional importance of the reversible mRNA m6A methylation and its modulators in ischemic heart disease.
Responsed Disease	Ischemic heart disease [ICD-11: BA40-BA6Z]
Target Regulator	RNA demethylase ALKBH5 (ALKBH5)		ERASER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Apoptosis			hsa04210)
Cell Process	Cell proliferation
In-vitro Model	H9c2(2-1)	Normal	Rattus norvegicus	CVCL_0286
	HEK293T	Normal	Homo sapiens	CVCL_0063
In-vivo Model	To cause I/R injury, mice were subjected to 30 min of LAD ischemia followed by 60 min of reperfusion.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[4]
Response Summary	FTO down-expressed in myocardial IRI mice and hypoxia/reoxygenation (H/R)-induced cardiomyocytes. Moreover, FTO uninstalled the methylation of Transcriptional coactivator YAP1 (YAP1) mRNA, and enforced the stability of Yap1 mRNA.The study reveals the role of FTO in H/R-induced myocardial cell injury via m6A-dependent manner, which provided a new approach to improve myocardial IRI.
Responsed Disease	Ischemic heart disease [ICD-11: BA40-BA6Z]
Target Regulator	Fat mass and obesity-associated protein (FTO)		ERASER	Regulator Info
Target Regulation	Up regulation
Cell Process	Cell apoptosis
In-vitro Model	Neonatal rat ventricular cardiomyocytes (Primary myocyte cells)
In-vivo Model	After anesthesia (50 mg/kg pentobarbital sodium, intraperitoneal injection), the left thorax was cut to expose the heart, and the left anterior descending (LAD) coronary artery was ligated by 7/0 sterile suture. Myocardial ischemia was induced by 30 min of LAD coronary artery ligation and following 2 h of reperfusion. Sham group mice underwent the same surgical procedure without LAD coronary artery ligation.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[2]
Response Summary	METTL3 promoted DGCR8 binding to pri-miR-143-3p through m6A modification, thus enhancing hsa-miR-143-3p expression to inhibit PRKCE transcription and further aggravating cardiomyocyte pyroptosis and MI/R injury.
Responsed Disease	Ischemic heart disease [ICD-11: BA40-BA6Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Cell Process	Pyroptosis
In-vitro Model	H9c2(2-1)	Normal	Rattus norvegicus	CVCL_0286
In-vivo Model	The thoracic cavity of rats was exposed, and the left anterior descending coronary artery was ligated with a 6-0 silk thread. Successfully surgical MI could be observed, with myocardium color fading and pulse weakening. After 30 min of ischemia, the blood flow was restored by releasing the slipknot, and then 120-min perfusion was performed. Afterward, the thoracic cavity of rats was sutured. The rats were assigned into 4 groups, with 12 rats in each group. Lentivirus packaged short hairpin (sh)-negative control (NC) and sh-METTL3 (GenePharma, Shanghai, China) were injected into the rats via tail vein 24 h before operation. The titer of lentivirus was 1?×?109 TU/mL, and the injection rate was 0.2 ul/min for 10 min. Blood samples were collected 24 h after reperfusion.

Ref 1	Mettl14 Attenuates Cardiac Ischemia/Reperfusion Injury by Regulating Wnt1/Beta-Catenin Signaling Pathway. Front Cell Dev Biol. 2021 Dec 16;9:762853. doi: 10.3389/fcell.2021.762853. eCollection 2021.
Ref 2	Mechanism of METTL3-Mediated m(6)A Modification in Cardiomyocyte Pyroptosis and Myocardial Ischemia-Reperfusion Injury. Cardiovasc Drugs Ther. 2022 Jan 23. doi: 10.1007/s10557-021-07300-0. Online ahead of print.
Ref 3	METTL3 and ALKBH5 oppositely regulate m(6)A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes. Autophagy. 2019 Aug;15(8):1419-1437. doi: 10.1080/15548627.2019.1586246. Epub 2019 Mar 17.
Ref 4	m(6)A demethylase FTO regulates the apoptosis and inflammation of cardiomyocytes via YAP1 in ischemia-reperfusion injury. Bioengineered. 2022 Mar;13(3):5443-5452. doi: 10.1080/21655979.2022.2030572.