Affinage

TNNI3

Troponin I, cardiac muscle · UniProt P19429

Round 2 corrected
Length
210 aa
Mass
24.0 kDa
Annotated
2026-04-28
130 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNNI3 encodes cardiac troponin I (cTnI), the inhibitory subunit of the sarcomeric troponin complex that governs Ca²⁺-dependent regulation of cardiac muscle contraction. The cTnI switch peptide (residues 147–163) binds the N-terminal regulatory domain of troponin C in a Ca²⁺-dependent manner to induce its open conformation, while the inhibitory peptide (~residues 128–147) restrains actin–tropomyosin at low Ca²⁺; these interactions, resolved by crystal and NMR structures of the ternary troponin complex, are modulated by PKA phosphorylation at S23/S24 (governing length-dependent activation and the Frank–Starling mechanism), PKC phosphorylation at S43/S45 (reducing contractility), PAK3 phosphorylation at S151 (increasing Ca²⁺ sensitivity), and PRMT1-mediated arginine methylation at R146/R148 (PMID:10387074, PMID:12840750, PMID:23836688, PMID:14726296, PMID:20540949, PMID:30772011). cTnI is targeted for proteasomal degradation by the E3 ubiquitin ligase MuRF1, which assembles mixed-linkage polyubiquitin chains via UbcH5 whose topology determines degradation efficiency (PMID:15601779, PMID:17426036). Mutations throughout TNNI3 cause hypertrophic, restrictive, or dilated cardiomyopathy by altering Ca²⁺ sensitivity, thin-filament integrity, and diastolic relaxation, as demonstrated by family linkage studies, reconstituted fiber mechanics, and CRISPR-corrected patient iPSC-cardiomyocyte models (PMID:9241277, PMID:12531876, PMID:32182250, PMID:38193576).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 Medium

    Defining the genomic organization and cardiac-enriched promoter of TNNI3 established a framework for understanding its transcriptional regulation, revealing that 2.3 kb of 5′-flanking sequence drives expression in cardiac but not non-muscle cells, though full cardiac specificity required additional elements.

    Evidence Genomic cloning, sequencing, and transfection reporter assays in cardiac myocytes and fibroblasts

    PMID:8661099

    Open questions at the time
    • Minimal regulatory elements sufficient for cardiac specificity not mapped
    • No in vivo transgenic validation of promoter constructs
  2. 1997 High

    Identification of TNNI3 mutations in HCM families established cTnI as a disease gene and demonstrated that the inhibitory subunit of the troponin complex is essential for normal cardiac function, opening the mechanistic question of how specific residue changes alter contractility.

    Evidence Candidate gene sequencing in 184 unrelated HCM patients with family linkage analysis

    PMID:9241277

    Open questions at the time
    • Molecular mechanism by which individual mutations (e.g., R145G) alter troponin function not yet determined
    • No functional reconstitution at this stage
  3. 1998 High

    The first crystal structure of a TnC–TnI fragment complex revealed that TnI binding converts TnC from an elongated to a compact globular conformation, providing the first atomic-level view of how the inhibitory subunit contacts both lobes of TnC.

    Evidence X-ray crystallography at 2.3 Å resolution with MAD phasing

    PMID:9560191

    Open questions at the time
    • Only N-terminal TnI fragment (1–47) resolved; inhibitory and switch peptide regions not visualized
    • No Ca²⁺-dependent conformational changes captured
  4. 1999 High

    NMR resolution of the cTnI switch peptide (147–163) bound to the Ca²⁺-loaded cTnC N-terminal domain revealed that cTnI binding—not Ca²⁺ alone—induces the open conformation of cNTnC, establishing the molecular basis for Ca²⁺-dependent activation of cardiac muscle.

    Evidence Multinuclear multidimensional NMR spectroscopy and solution structure determination

    PMID:10387074

    Open questions at the time
    • Isolated peptide–domain complex; behavior in the context of the full troponin–tropomyosin–actin filament not addressed
    • Inhibitory peptide conformation not resolved simultaneously
  5. 2003 High

    Two landmark advances: the crystal structure of the ternary cardiac troponin core domain revealed the IT arm coiled-coil architecture and Ca²⁺-dependent release of cTnI from actin, while genetic linkage and multi-family screening established TNNI3 as a cause of restrictive cardiomyopathy in addition to HCM.

    Evidence X-ray crystallography of ternary troponin core domain (Nature); linkage analysis (LOD 4.8) plus mutation screening in RCM families (JCI)

    PMID:12531876 PMID:12840750

    Open questions at the time
    • Full-length troponin on the thin filament not structurally resolved
    • Mechanism by which the same gene causes HCM vs. RCM not clarified at structural level
  6. 2004 High

    Parallel discoveries showed that cTnI is a substrate of the E3 ubiquitin ligase MuRF1 (linking proteasomal degradation to contractile protein turnover) and that PKC phosphorylation at S43/S45 attenuates contractility in vivo, with cross-talk between PKC and PKA phosphorylation sites.

    Evidence Yeast two-hybrid, co-IP, in vitro ubiquitylation, and cardiomyocyte contractility assays for MuRF1; transgenic S43A/S45A mice with in situ hemodynamics for PKC sites

    PMID:14726296 PMID:15601779

    Open questions at the time
    • Physiological signals controlling MuRF1-mediated cTnI turnover rates in vivo unclear
    • PKC isoform specificity for S43/S45 phosphorylation in intact heart not defined
  7. 2007 High

    Reconstitution of MuRF1-mediated ubiquitylation with defined E2 enzymes revealed that ubiquitin chain topology (mixed forked chains via UbcH5 vs. homogeneous K48 or K63 chains) determines cTnI degradation efficiency by the 26S proteasome, adding a regulatory layer to sarcomeric protein quality control.

    Evidence In vitro ubiquitylation with purified components, mass spectrometry of chain linkages, 26S proteasome degradation assays

    PMID:17426036

    Open questions at the time
    • In vivo chain type preference on endogenous cTnI not confirmed
    • Whether deubiquitinases selectively edit specific chain types on cTnI is unknown
  8. 2010 High

    PAK3-mediated phosphorylation of cTnI at S151 was shown to increase myofilament Ca²⁺ sensitivity by shortening inter-site cTnC–cTnI distances and slowing Ca²⁺-dissociation-induced structural transitions, mimicking the effect of strong crossbridges and identifying a third kinase-specific regulatory input on cTnI.

    Evidence Steady-state and time-resolved FRET, stopped-flow kinetics in reconstituted thin filaments with S151E phosphomimetic

    PMID:20540949

    Open questions at the time
    • In vivo contribution of PAK3 to cTnI phosphorylation at S151 under physiological stimuli not quantified
    • Interplay between S151 phosphorylation and S23/S24 or S43/S45 not tested
  9. 2013 High

    PKA phosphorylation of cTnI at S23/S24 was established as the molecular switch for length-dependent Ca²⁺ sensitivity (Frank–Starling mechanism), as unphosphorylated troponin exchange abolished steep length–tension relationships that were restored by PKA treatment or phosphomimetic substitution.

    Evidence Troponin exchange in permeabilized cardiac myocytes and skeletal fibers, PKA treatment, S23D/S24D phosphomimetics, force-length measurements

    PMID:23836688

    Open questions at the time
    • Structural mechanism by which N-terminal extension phosphorylation transmits length sensing to the regulatory domain not resolved
    • Contribution of titin compliance to the observed effects not dissected
  10. 2015 Medium

    MD simulations of the R145G HCM mutation provided a molecular explanation for its blunted β-adrenergic response: R145G stabilizes Ca²⁺ coordination in cTnC and prevents PKA-phosphorylation-induced intramolecular contact between the N-terminal extension and the inhibitory peptide, consistent with experimental observation of impaired β-adrenergic modulation in R145G cardiomyocytes.

    Evidence Triplicate 150 ns molecular dynamics simulations of troponin subcomplexes with R145G and phosphomimetic variants; complemented by earlier cardiomyocyte sarcomere shortening data

    PMID:18548271 PMID:25606687

    Open questions at the time
    • Computational prediction; direct experimental validation of altered intramolecular contacts in full-length cTnI-R145G lacking
    • Simulations limited to 150 ns timescale
  11. 2016 Medium

    Epigenetic regulation of TNNI3 transcription was uncovered: HDAC5 binds the cTnI promoter and deacetylates H3K9, repressing transcription—an effect reversed by HDAC inhibitor SAHA—adding a transcriptional regulatory layer to cTnI biology.

    Evidence ChIP, HDAC activity assays, RT-PCR, Western blot, and HDAC inhibitor treatment in neonatal mouse hearts

    PMID:27379430

    Open questions at the time
    • Physiological contexts in which HDAC5 is recruited to the TNNI3 promoter beyond estrogen exposure unclear
    • Whether HDAC5 directly binds DNA or is recruited via a transcription factor complex not determined
  12. 2017 Medium

    HDAC1 and HDAC3 were further implicated in TNNI3 promoter repression, with GATA4 and MEF2C binding shown to activate transcription when HDAC-mediated deacetylation is relieved, defining a complete activator–repressor switch at the TNNI3 locus.

    Evidence ChIP, Western blot, echocardiography, and EGCG treatment in aged mice

    PMID:28382690

    Open questions at the time
    • Direct HDAC1/3 recruitment mechanism not resolved
    • Whether age-related cTnI decline is a cause or consequence of cardiac dysfunction not established
  13. 2019 Medium

    Three concurrent advances expanded cTnI biology: (1) arginine methylation at R146/R148 by PRMT1 was discovered in human myocardium, with HCM mutations at R145 impairing this modification and methylation-deficient cTnI inducing hypertrophy; (2) nuclear cTnI was shown to interact with SMYD1 and HDAC1, epigenetically regulating PDE4d expression; (3) complete loss of cTnI protein in a patient with a homozygous truncating variant triggered compensatory re-expression of fetal TNNI1.

    Evidence Mass spectrometry, in vitro PRMT1 assays, H9c2 cell transfection (PMID:30772011); nuclear fractionation, co-IP, ChIP in RCM mice (PMID:30900165); Western blot/transcript analysis of endomyocardial biopsy (PMID:31568572)

    PMID:30772011 PMID:30900165 PMID:31568572

    Open questions at the time
    • Nuclear cTnI findings require independent replication and quantification of nuclear vs. sarcomeric pools
    • Functional consequence of R146/R148 methylation on thin filament Ca²⁺ regulation not tested in reconstituted systems
    • Whether TNNI1 compensation is sufficient for long-term cardiac function unknown
  14. 2020 High

    Reconstitution and EM studies of RCM-associated R170G/W mutations showed increased tropomyosin affinity, disrupted thin filament structural integrity, and loss of cMyBP-C regulatory modulation—demonstrating that a single cTnI residue change can simultaneously affect multiple protein–protein interfaces within the thin filament.

    Evidence Skinned fiber mechanics, reconstituted thin filament EM, co-sedimentation, microscale thermophoresis

    PMID:32182250

    Open questions at the time
    • Whether loss of MyBP-C modulation is a general feature of RCM mutations or specific to R170 unclear
    • In vivo consequence of altered thin filament integrity not assessed in animal model
  15. 2024 High

    Patient-derived iPSC-cardiomyocyte and engineered heart tissue models of TNNI3 R170W RCM demonstrated that the mutation directly causes diastolic dysfunction (prolonged relaxation), which was reversed by CRISPR isogenic correction and wild-type TNNI3 overexpression, establishing a causal link from genotype to diastolic phenotype and validating gene augmentation as a potential therapeutic strategy.

    Evidence iPSC-CM generation, CRISPR/Cas9 isogenic correction, EHT formation, Ca²⁺ kinetics imaging, force measurements, TNNI3 overexpression rescue

    PMID:38193576 PMID:38497452

    Open questions at the time
    • Long-term in vivo efficacy of TNNI3 gene augmentation not tested
    • Whether TNNI3 overexpression causes dominant-negative effects at supraphysiological levels not evaluated
    • Transcriptomic changes (TGF-β, ECM pathways) observed in mutant cells await mechanistic dissection

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for how individual TNNI3 mutations differentially cause HCM, RCM, or DCM; the physiological significance and regulation of nuclear cTnI; the in vivo dynamics and chain-type specificity of MuRF1-mediated cTnI turnover; and whether gene therapy or allele-specific silencing can correct TNNI3-associated cardiomyopathies.
  • No high-resolution cryo-EM structure of the full thin filament with disease-mutant troponin
  • Nuclear cTnI interactome and gene regulatory targets not comprehensively mapped
  • No clinical gene therapy trials for TNNI3 cardiomyopathies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 3 GO:0005198 structural molecule activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005634 nucleus 1
Pathway
R-HSA-397014 Muscle contraction 8 R-HSA-1643685 Disease 6 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
HDAC1MYBPC3PRMT1RCAN3SMYD1TNNC1TNNT2TRIM63
Complex memberships
cardiac troponin complex (cTnC–cTnI–cTnT)thin filament (troponin–tropomyosin–actin)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 The human cardiac troponin I gene (TNNI3) comprises eight exons within 6.2 kb of genomic DNA. Transfection experiments showed that 2300 bp of 5'-flanking sequence drives expression in cardiac myocytes and skeletal muscle cells but not fibroblasts, and several conserved putative cis-acting elements were identified in the proximal promoter, indicating that additional sequences are required to confer cardiac specificity. Genomic cloning, sequencing, transfection reporter assays in cardiac myocytes and fibroblasts Genomics Medium 8661099
1997 Mutations in TNNI3 (cardiac troponin I) were identified as a cause of hypertrophic cardiomyopathy, establishing cTnI as an HCM disease gene. Key mutations included Arg145Gly (linked by family analysis) and Lys206Gln (de novo), demonstrating that the inhibitory subunit of the troponin complex is essential for normal cardiac function. Candidate gene sequencing in 184 unrelated HCM patients, family linkage analysis, identification of de novo mutations Nature genetics High 9241277
1998 The crystal structure of troponin C in complex with the N-terminal fragment of troponin I (TnI residues 1–47) at 2.3 Å resolution revealed that TnC adopts a compact globular conformation (vs. elongated dumbbell in free TnC) with the central helix bent 90°. The TnI1–47 alpha-helix spans the surface of TnC, stabilizing the compact conformation via contacts with both N- and C-terminal lobes, with the amphiphilic C-terminus of TnI1–47 anchored in the hydrophobic pocket of the TnC C-lobe. X-ray crystallography (2.3 Å), single isomorphous replacement + MAD phasing Proceedings of the National Academy of Sciences of the United States of America High 9560191
1999 NMR structure of the cardiac TnC N-terminal regulatory domain (cNTnC) in complex with Ca2+ and the cTnI switch peptide (residues 147–163) showed that cTnI147–163 binding induces an 'open' conformation of cNTnC (similar to Ca2+-saturated skeletal TnC), even though Ca2+ alone does not open cNTnC. The cTnI peptide adopts an alpha-helical conformation at residues 150–157 bound in the hydrophobic pocket of cNTnC, establishing the molecular basis for Ca2+-dependent activation of cardiac muscle. Multinuclear multidimensional NMR spectroscopy, solution structure determination Biochemistry High 10387074
2003 The crystal structure of the core domain of human cardiac troponin (TnC + TnI + TnT) in the Ca2+-saturated form revealed that the core domain is divided into structurally distinct subdomains connected by flexible linkers. An alpha-helical coiled-coil between TnT and TnI forms the rigid IT arm (~80 Å), which bridges tropomyosin-anchoring regions. Ca2+ binding to the regulatory site of TnC removes the C-terminal portion of TnI from actin, altering mobility/flexibility of troponin and tropomyosin on the actin filament. X-ray crystallography (crystal structures at 46 kDa and 52 kDa core domain constructs) Nature High 12840750
2003 TNNI3 mutations were identified as causes of idiopathic restrictive cardiomyopathy (RCM). In a large family with both RCM and HCM, linkage to TNNI3 was established (lod score 4.8) and a novel missense mutation identified. Screening nine additional unrelated RCM patients found TNNI3 mutations in six, including two de novo mutations in young patients. All mutations mapped to conserved, functionally important domains, establishing TNNI3 as an RCM susceptibility gene. Linkage analysis, candidate gene mutation screening, family co-segregation studies The Journal of clinical investigation High 12531876
2004 Muscle-specific RING finger protein 1 (MuRF1) was identified as a bona fide ubiquitin E3 ligase that ubiquitylates and degrades cardiac troponin I (cTnI). Yeast two-hybrid screening identified cTnI as a MuRF1 interactor; co-IP confirmed the association in vitro and in cardiomyocytes. MuRF1 reduced steady-state cTnI levels via RING finger-dependent ubiquitin ligase activity, accumulation of poly-ubiquitylated cTnI intermediates, and proteasome-dependent degradation. MuRF1 overexpression in cardiomyocytes reduced contractility indices. Yeast two-hybrid screen, Co-immunoprecipitation, in vitro ubiquitylation assay, cardiomyocyte overexpression with contractility readout Proceedings of the National Academy of Sciences of the United States of America High 15601779
2004 PKC phosphorylation of cTnI at Ser43 and Ser45 modulates cardiac contractility in vivo. Transgenic mice with Ala substitutions at these sites (preventing PKC phosphorylation) showed 30% greater +dP/dt and 18% greater −dP/dt at baseline compared with wild-type, and had negligible inotropic response to isoproterenol or phenylephrine/propranolol. Mutation of PKC sites was also associated with enhanced PKA-dependent phosphorylation of cTnI, demonstrating interdependence of phosphorylation sites. Transgenic mouse model (Ala substitutions at S43/S45), in situ hemodynamics, back-phosphorylation assays, cAMP measurements American journal of physiology. Heart and circulatory physiology High 14726296
2006 DSCR1L2 (Down Syndrome Critical Region gene 1-like 2) protein interacts directly with cardiac troponin I (TNNI3). Interaction was identified by yeast two-hybrid screening of a human heart cDNA library and confirmed by yeast co-transformation and GST fusion protein pull-down assays. A novel DSCR1L2 splice isoform lacking two central exons was identified; both isoforms interact with TNNI3, and exon 2 of DSCR1L2 is critical for binding, suggesting a possible role for this calcineurin-pathway family member in cardiac contraction. Yeast two-hybrid screening (human heart cDNA library), yeast co-transformation, GST pulldown assay, quantitative RT-PCR Gene Medium 16516408
2007 A novel one-nucleotide frameshift deletion in TNNI3 (exon 7) causing premature stop codon and truncation of the C-terminal portion of cTnI was found to cause restrictive cardiomyopathy. Western blot analysis of myocardial tissue showed approximately 50% reduction in total troponin I content, indicating haploinsufficiency of cTnI protein as a mechanism for RCM. Candidate gene sequencing, Western blot of myocardial tissue International journal of cardiology Medium 18006163
2007 MuRF1 with the E2 enzyme UbcH5 synthesizes mixed forked ubiquitin chains on troponin I containing all seven possible linkages (predominantly Lys48, Lys63, Lys11), and troponin I linked to these forked chains was degraded poorly by purified 26S proteasomes compared to troponin I linked to homogeneous Lys48 or Lys63 chains. With UbcH13/Uev1a, MuRF1 attaches Lys63 chains, and with UbcH1 it attaches Lys48 chains, both of which support efficient degradation, establishing that chain topology determines proteasomal degradation efficiency of cTnI. In vitro ubiquitylation assay with purified components, mass spectrometry of Ub chain linkages, 26S proteasome degradation assay The Journal of biological chemistry High 17426036
2008 Expression of the HCM-associated cTnI-R145G mutation in adult rat cardiomyocytes significantly decreased baseline sarcomere shortening. Upon β-adrenergic stimulation with isoproterenol, rates of shortening and re-lengthening were depressed in cTnI-R145G-expressing cells but comparable to controls when using the β2-selective blocker ICI118,551, indicating that the R145G mutation alters β-adrenergic receptor subtype-dependent modulation of contractility. Adenovirus-mediated expression of cTnI-R145G in adult rat cardiomyocytes, sarcomere shortening measurements, pharmacological β-adrenergic dissection Pflugers Archiv : European journal of physiology Medium 18548271
2010 PAK3-mediated phosphorylation of cTnI at Ser151 (studied via S151E phosphomimic) increases Ca2+ sensitivity of myofilament by shortening inter-site distances between cTnC and cTnI (monitored by FRET in reconstituted thin filaments) and reducing kinetic rates of Ca2+-dissociation-induced structural changes in the regulatory region of cTnI. The structural effects mimic those of strong actomyosin crossbridges. Steady-state and time-resolved FRET, stopped-flow kinetics in reconstituted thin filaments containing cTnI-S151E Journal of molecular biology High 20540949
2013 Phosphorylation of cTnI at serines 23/24 by PKA is a key regulator of length dependence of force generation (Frank-Starling mechanism) in cardiac myocytes. Exchange of unphosphorylated recombinant cTn into permeabilized rat cardiac myocytes or slow-twitch skeletal muscle fibers produced a shallow length-tension relationship; PKA treatment or use of cTn with S23/S24 mutated to Asp (phosphomimetic) restored a steep length-tension relationship. Troponin exchange into permeabilized cardiac myocytes and skeletal muscle fibers, PKA treatment, phosphomimetic mutation (S23D/S24D), force-length measurements The Journal of physiology High 23836688
2014 The Ca2+-regulatory function of the cTnI inhibitory peptide (Ip) region requires cooperation with the C-terminus of cTnT. In vitro motility assays showed that cTnI-R145G (within the Ip) alone impaired switching off of actomyosin at low Ca2+; cTnT-R278C partially rescued high-Ca2+ defects of cTnI-R145G but exacerbated loss of inhibitory function at low Ca2+. Bioinformatics analysis revealed evolutionary and structural relatedness between the affected regions of cTnI and cTnT. In vitro motility assay with reconstituted troponin complexes (single and double mutants), varying Ca2+ concentration, temperature, and HMM density Archives of biochemistry and biophysics Medium 24418317
2015 Molecular dynamics simulations of the cTnI-R145G HCM mutation revealed that R145G does not alter overall cTn dynamics but stabilizes Ca2+-coordinating interactions in cTnC. The R145G mutation blunted intramolecular interactions between the cTnI N-terminal extension (residues 1–39) and the inhibitory peptide that are normally induced by PKA phosphorylation of S23/S24 (β-adrenergic signaling), providing a molecular explanation for why R145G reduces β-adrenergic modulation of cTn. Triplicate 150 ns molecular dynamics simulations of cTnC(1–161)–cTnI(1–172)–cTnT(236–285) complexes with R145G, R145G/S23D/S24D, and R145G/pS23/pS24 Biophysical journal Medium 25606687
2015 TNNI3 encodes the inhibitory subunit of the troponin complex and has evolved from TNNI1 and TNNI2 (slow and fast skeletal isoforms) through vertebrate evolution. cTnI has a unique N-terminal cardiac-specific extension (residues 1–32) that is phosphorylated by PKA at S23/S24 and by PKC at S43/S45, and contains an inhibitory peptide region and a switch peptide that interact with cTnC. Developmental regulation switches expression from slow skeletal TNNI1 to TNNI3 postnatally in cardiac muscle. Comparative genomic and phylogenetic analysis, review of biochemical and PTM literature Gene Medium 26526134
2016 In cardiomyocytes from cTnI-G203S HCM mice, L-type Ca2+ channel (ICaL) inactivation was significantly faster. Activation of ICaL caused a greater increase in mitochondrial membrane potential and metabolic activity in cTnI-G203S myocytes compared to wild-type. This hypermetabolic response resulted from impaired communication between ICaL and F-actin, involving reduced actin-myosin dynamics and block of the mitochondrial voltage-dependent anion channel. L-type Ca2+ channel antagonists normalized mitochondrial membrane potential. Patch-clamp electrophysiology, mitochondrial membrane potential measurements, metabolic activity assays, pharmacological manipulation (nisoldipine, diltiazem) in isolated cardiomyocytes from transgenic cTnI-G203S mice The Journal of physiology Medium 27062056
2016 Estrogen treatment of neonatal mouse hearts increased HDAC activity and HDAC5 binding at the cTnI promoter, reduced histone H3K9 acetylation at the cTnI promoter, and decreased cTnI expression at both mRNA and protein levels. SAHA (an HDAC inhibitor) rescued cTnI expression by inhibiting HDAC5 binding and restoring H3K9 acetylation at the cTnI promoter, indicating that HDAC5-mediated histone deacetylation represses TNNI3 transcription. Chromatin immunoprecipitation (ChIP), colorimetric HDAC/HAT activity assays, RT-PCR, Western blot, pharmacological HDAC inhibition in neonatal mouse hearts Journal of cellular biochemistry Medium 27379430
2017 EGCG (epigallocatechin-3-gallate) improved cardiac diastolic function in aged mice by reversing age-related low cTnI expression. Mechanistically, EGCG inhibited HDAC1 and HDAC3 expression and reduced HDAC1 binding to the cTnI proximal promoter, increased H3K9 acetylation at the promoter, and enhanced binding of transcription factors GATA4 and Mef2c to the cTnI promoter. ChIP assay, Western blot, echocardiography, HDAC1/HDAC3 expression analysis, transcription factor binding assay in aged mice treated with EGCG Journal of cellular and molecular medicine Medium 28382690
2019 cTnI is modified by arginine methylation in human myocardium. Mass spectrometry identified methylation sites at R74/R79 and R146/R148 in human cardiac samples. PRMT1 methylated an extended cTnI inhibitory peptide at R146 and R148 in vitro. HCM-associated mutations at R145 hampered R146/R148 methylation by PRMT1 in vitro. Methylation-deficient R146A/R148A cTnI expressed in H9c2 cells induced a 32% increase in cell size (hypertrophy), and Western blot showed reduced arginine methylation levels in HCM vs. DCM biopsies and in a rat cardiac hypertrophy model. Western blot with anti-methylarginine antibody, mass spectrometry, in vitro PRMT1 methylation assay, cell size measurement in H9c2 cells transfected with methylation-deficient mutant International journal of cardiology Medium 30772011
2019 In restrictive cardiomyopathy mice carrying the cTnI-193His mutation, PDE4d expression was epigenetically downregulated. cTnI was detected in the nucleus of cardiomyocytes by immunofluorescence and Western blot. Co-immunoprecipitation demonstrated direct interaction between cTnI and SMYD1 (histone methyltransferase) and between cTnI and HDAC1. Overexpression of mutated cTnI in cultured cardiomyocytes reduced PDE4d expression, suggesting nuclear cTnI modulates histone modifications and gene expression via interaction with chromatin-modifying enzymes. Immunofluorescence, Western blot of nuclear fractions, Co-IP, ChIP, cardiomyocyte overexpression studies Science China. Life sciences Medium 30900165
2019 Panel sequencing of 80 pediatric cardiomyopathy patients identified 5 pathogenic TNNI3 variants; one patient carried a homozygous truncating variant (c.24+2T>A). Protein and transcript analysis on heart biopsies from this individual showed complete absence of TNNI3 protein and compensatory upregulation of the fetal slow skeletal isoform TNNI1, demonstrating that total loss of cTnI triggers a developmental isoform switch. Next-generation sequencing panel, Western blot and transcript analysis of endomyocardial biopsy Clinical genetics Medium 31568572
2020 RCM-associated cTnI mutations R170G and R170W (in the regulatory C-terminus) strongly enhanced Ca2+ sensitivity in skinned cardiac fibers. Both mutants increased affinity of the troponin complex for tropomyosin; R170G strengthened and R170W weakened actin binding. Electron microscopy of reconstituted thin filaments showed wavy, broken filaments with R170G/W. MyBP-C N-terminal fragment (cMyBPC-C0C2) that normally reduces troponin binding to actin and increases cooperativity of thin filament activation had no effect in the presence of R170G/W cTn, and microscale thermophoresis identified direct cMyBPC-C0C2 binding to cTnI and cTnT (but not cTnC). Skinned fiber Ca2+-sensitivity measurements, electron microscopy of reconstituted thin filaments, co-sedimentation assays, microscale thermophoresis PloS one High 32182250
2020 miR-449 regulates cTnI expression in cardiomyocytes by targeting HDAC1. miR-449 sponges HDAC1, relieving HDAC1-mediated deacetylation of H3K4 and H3K9 at the cTnI promoter GATA element, which in turn recruits transcription factor GATA4 to increase TNNI3 transcription. In vivo, miR-449 agomiR intervention in aged mice with low cTnI expression restored cTnI levels and improved cardiac function. Dual-luciferase reporter assay (miR-449/HDAC1 binding site), biochemical analysis, in vivo miR-449 agomiR injection in aged mice, echocardiography European review for medical and pharmacological sciences Medium 33378032
2021 De novo cTnI-D127Y mutation (infantile restrictive cardiomyopathy) increased Ca2+ sensitivity and reduced maximum force in skinned cardiomyocytes. In reconstituted thin filaments, cTnI-D127Y showed increased actin/tropomyosin binding affinity and compromised structural integrity (EM). Levosimendan and EGCG (troponin-targeting agents) partially stabilized thin filament structure and improved contractile parameters in vitro for both cTnI-D127Y and the companion cTnC-G34S mutation. Skinned fiber mechanics, reconstituted thin filament assays, electron microscopy, protein interaction binding assays, pharmacological intervention (levosimendan, EGCg) International journal of molecular sciences Medium 34502534
2024 iPSC-derived cardiomyocytes and engineered heart tissues (EHT) from a patient carrying TNNI3 R170W showed prolonged tau (relaxation time constant) in Ca2+ kinetics and an increased ratio of relaxation force to contractile force. CRISPR/Cas9 isogenic correction of R170W reversed these defects. Overexpression of wild-type TNNI3 in R170W-iPSC-CMs and EHTs also rescued impaired relaxation, demonstrating that cTnI levels and function directly determine diastolic dysfunction in RCM. iPSC generation, CRISPR/Cas9 isogenic correction, EHT formation, Ca2+ kinetics imaging, force measurements, TNNI3 overexpression rescue Development, growth & differentiation High 38193576
2024 Patient-specific iPSC-derived cardiomyocytes heterozygous and homozygous for TNNI3 R170W showed impaired diastolic function (cell motion analysis) compared to CRISPR-corrected isogenic lines and three independent healthy controls. Intracellular Ca2+ oscillation and troponin I immunocytochemistry were not significantly altered, and myofibril/mitochondrial ultrastructure appeared intact by electron microscopy, but RNA-seq revealed altered pathways in cardiac muscle development/contraction, extracellular matrix-receptor interaction, and TGF-β signaling. iPSC-CM differentiation, CRISPR/Cas9 isogenic lines, cell motion analysis, Ca2+ imaging, immunocytochemistry, electron microscopy, RNA sequencing Journal of the American Heart Association Medium 38497452

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2003 Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 969 12707239
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2003 Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form. Nature 659 12840750
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circulation research 646 12242268
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