Title: A Roadmap for Fixing the Heart: RNA Regulatory Networks in Cardiac Disease
Abstract: With the continuous development of RNA biology and massive genome-wide transcriptome analysis, more and more RNA molecules and their functions have been explored in the last decade. Increasing evidence has demonstrated that RNA-related regulatory networks play an important role in a variety of human diseases, including cardiovascular diseases. In this review, we focus on RNA regulatory networks in heart disease, most of which are devastating conditions with no known cure. We systemically summarize recent discoveries of important new components of RNA regulatory networks, including microRNAs, long non-coding RNAs, and circular RNAs, as well as multiple regulators that affect the activity of these networks in cardiac physiology and pathology. In addition, this review covers emerging micropeptides, which represent short open reading frames (sORFs) in long non-coding RNA transcripts that may modulate cardiac physiology. Based on the current knowledge of RNA regulatory networks, we think that ongoing discoveries will not only provide us a better understanding of the molecular mechanisms that underlie heart disease, but will also identify novel biomarkers and therapeutic targets for the diagnosis and treatment of cardiac disease. With the continuous development of RNA biology and massive genome-wide transcriptome analysis, more and more RNA molecules and their functions have been explored in the last decade. Increasing evidence has demonstrated that RNA-related regulatory networks play an important role in a variety of human diseases, including cardiovascular diseases. In this review, we focus on RNA regulatory networks in heart disease, most of which are devastating conditions with no known cure. We systemically summarize recent discoveries of important new components of RNA regulatory networks, including microRNAs, long non-coding RNAs, and circular RNAs, as well as multiple regulators that affect the activity of these networks in cardiac physiology and pathology. In addition, this review covers emerging micropeptides, which represent short open reading frames (sORFs) in long non-coding RNA transcripts that may modulate cardiac physiology. Based on the current knowledge of RNA regulatory networks, we think that ongoing discoveries will not only provide us a better understanding of the molecular mechanisms that underlie heart disease, but will also identify novel biomarkers and therapeutic targets for the diagnosis and treatment of cardiac disease. Cardiac disease is the leading cause of death and disease around the world. In response to external stress or stimulus, the heart maintains homeostasis through dynamic remodeling. 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Shen W.K. et al.Regulation of cardiac CACNB2 by microRNA-499: potential role in atrial fibrillation.BBA Clin. 2017; 7: 78-84Crossref PubMed Scopus (27) Google ScholarTHRAP1, thyroid hormone receptor-associated protein 1; MED13/NcoR1, mediator of transcription 13/nuclear receptor corepressor 1; FBLN2, fibulin-2; TWF1, twinfilin-1; CALM1/2, calmodulin 1/2; MYLK3, myosin light chain kinase 3; RasGAP, Ras GTPase-activating protein; MEF2A, myocyte enhancer factor 2; Cdk9, cyclin-dependent kinase 9; Rheb, Ras homolog enriched in brain; CF, cardiac fibroblast; SPRY1, sprouty homolog 1; mt-Cytb, mtDNA-encoded cytochrome b; CTGF, connective tissue growth factor; RHOA, a GDP-GTP exchange protein associated with cardiac growth; CDC42, a signaling kinase involved in pathological hypertrophy; NELF-A/WHSC2, a nuclear factor correlated with cardiogenesis; Jarid2, jumonji, AT-rich interactive domain 2; TP53INP1, tumor protein p53-inducible nuclear protein 1; HMBOX1, homeobox containing 1; HIPK1/2, homeodomain interacting protein kinase 1/2; JNK1, c-Jun N-terminal kinase 1; ETS-1, ETS proto-oncogene 1; SIRT3/4, sirtuin 3/4; MYOCD, myocardin; Bcl-2, B cell CLL/lymphoma 2; BAX, BCL2-associated X; QKI15, RNA-binding protein Quaking 15; CHD9, chromodomain helicase DNA-binding protein 9; ERRFI1, ERBB receptor feedback inhibitor 1; CnAα/β, calcineurin catalytic subunits; PDCD4, programmed cell death 4; PACS2, phosphofurin acidic cluster sorting protein 2; CHEK1, checkpoint kinase 1; β2-AR, β2 adrenergic receptor; MFN2, mitofusin 2; ARL2, ADP-ribosylation factor-like protein 2; MAPK3, mitogen-activated protein kinase 3; CIAPIN1, cytokine-induced apoptosis inhibitor 1; GJA1, gap junction protein α1; KCNJ2, potassium inwardly rectifying channel subfamily J member 2; HCN2/HCN4, hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2/4; NCX1, sodium/calcium exchanger protein; CACNA1C, calcium voltage-gated channel subunit α1C; IRX5, iroquois homeobox 5; CACNB2, voltage-dependent calcium channel β2 subunit; Cacna1c, calcium voltage-gated channel subunit 1C; Cacnb2, calcium voltage-gated channel auxiliary subunit 2; KCNN3, potassium calcium-activated channel subfamily N member 3. Open table in a new tab THRAP1, thyroid hormone receptor-associated protein 1; MED13/NcoR1, mediator of transcription 13/nuclear receptor corepressor 1; FBLN2, fibulin-2; TWF1, twinfilin-1; CALM1/2, calmodulin 1/2; MYLK3, myosin light chain kinase 3; RasGAP, Ras GTPase-activating protein; MEF2A, myocyte enhancer factor 2; Cdk9, cyclin-dependent kinase 9; Rheb, Ras homolog enriched in brain; CF, cardiac fibroblast; SPRY1, sprouty homolog 1; mt-Cytb, mtDNA-encoded cytochrome b; CTGF, connective tissue growth factor; RHOA, a GDP-GTP exchange protein associated with cardiac growth; CDC42, a signaling kinase involved in pathological hypertrophy; NELF-A/WHSC2, a nuclear factor correlated with cardiogenesis; Jarid2, jumonji, AT-rich interactive domain 2; TP53INP1, tumor protein p53-inducible nuclear protein 1; HMBOX1, homeobox containing 1; HIPK1/2, homeodomain interacting protein kinase 1/2; JNK1, c-Jun N-terminal kinase 1; ETS-1, ETS proto-oncogene 1; SIRT3/4, sirtuin 3/4; MYOCD, myocardin; Bcl-2, B cell CLL/lymphoma 2; BAX, BCL2-associated X; QKI15, RNA-binding protein Quaking 15; CHD9, chromodomain helicase DNA-binding protein 9; ERRFI1, ERBB receptor feedback inhibitor 1; CnAα/β, calcineurin catalytic subunits; PDCD4, programmed cell death 4; PACS2, phosphofurin acidic cluster sorting protein 2; CHEK1, checkpoint kinase 1; β2-AR, β2 adrenergic receptor; MFN2, mitofusin 2; ARL2, ADP-ribosylation factor-like protein 2; MAPK3, mitogen-activated protein kinase 3; CIAPIN1, cytokine-induced apoptosis inhibitor 1; GJA1, gap junction protein α1; KCNJ2, potassium inwardly rectifying channel subfamily J member 2; HCN2/HCN4, hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2/4; NCX1, sodium/calcium exchanger protein; CACNA1C, calcium voltage-gated channel subunit α1C; IRX5,