The Involvement of Krüppel-like Factors in Cardiovascular Diseases

Santoyo-Suarez, Michelle Giovanna; Mares-Montemayor, Jimena D.; Padilla‐Rivas, Gerardo R.; Delgado-Gallegos, Juan Luis; Quiroz-Reyes, Adriana G.; Roacho-Pérez, Jorge A.; Benítez-Chao, Diego Francisco; Garza-Ocañas, Lourdes; Arevalo-Martinez, Gilberto; Garza-Treviño, Elsa N.; Islas, José Francisco

doi:10.3390/life13020420

Cited by 15 publications

(23 citation statements)

References 143 publications

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“…Another TF identified in this analysis was GATA Binding Protein 4 ( GATA4 ) which is known to play a pivotal role in cardiac progenitor cells specification and cardiac septation (40). Additionally, our analysis revealed a significant over-representation of TFBSs from the Kruppel-like factor ( KLF ) family, recognized for their specialized roles in heart development (41). These included KLF2 (42,43), KLF4 (44,45), and KLF15 (46), the latter shown to be overexpressed during episodes of heart pressure overload, typically seen in hypertrophic cardiomyopathies.…”

Section: Resultsmentioning

confidence: 99%

Computational analysis of congenital heart disease associated SNPs: Unveiling their impact on the gene regulatory system

Vashisht,

Parisi,

Winata

2024

Preprint

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Congenital heart disease (CHD) is a prevalent condition characterized by defective heart development, causing premature death and stillbirths among infants. Genome-wide association studies (GWASs) have provided insights into the role of genetic variants in CHD pathogenesis through the identification of a comprehensive set of single-nucleotide polymorphisms (SNPs). Notably, 90-95% of these variants reside in the noncoding genome, complicating the understanding of their underlying mechanisms. Here, we developed a systematic computational pipeline for the identification and analysis of CHD-associated SNPs spanning both coding and noncoding regions of the genome. Initially, we curated a thorough dataset of SNPs from GWAS-catalog and ClinVar database and filtered them based on CHD-related traits. Subsequently, these CHD-SNPs were annotated and categorized into noncoding and coding regions based on their location. To study the functional implications of noncoding CHD-SNPs, we cross-validated them with enhancer-specific histone modification marks from developing human heart across 9 Carnegie stages and identified potential cardiac enhancers. This approach led to the identification of 2,056 CHD-associated putative enhancers (CHD-enhancers), 38.9% of them overlapping with known enhancers catalogued in human enhancer disease database. We identified heart-related transcription factor binding sites within these CHD-enhancers, offering insights into the impact of SNPs on TF binding. Conservation analysis further revealed that many of these CHD-enhancers were highly conserved across vertebrates, suggesting their evolutionary significance. Utilizing heart-specific expression quantitative trait loci data, we further identified a subset of 63 CHD-SNPs with regulatory potential distributed across various cardiac tissues. Concurrently, coding CHD-SNPs were represented as a protein interaction network and its subsequent binding energy analysis focused on a pair of proteins within this network, pinpointed a deleterious coding CHD-SNP, rs770030288, located in C2 domain of MYBPC3 protein. Overall, our findings demonstrate that SNPs have the potential to disrupt gene regulatory systems, either by affecting enhancer sequences or modulating protein-protein interactions, which can lead to abnormal developmental processes contributing to CHD pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Computational analysis of congenital heart disease associated SNPs: Unveiling their impact on the gene regulatory system

Vashisht,

Parisi,

Winata

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Another TF identi ed in this analysis was GATA Binding Protein 4 (GATA4) which is known to play a pivotal role in cardiac progenitor cells speci cation and cardiac septation (58). Additionally, our analysis revealed a signi cant over-representation of TFBSs from the Kruppel-like factor (KLF) family, recognized for their specialized roles in heart development (59). These included KLF2 (60, 61), KLF4 (62, 63), and KLF15 (64), the latter shown to be overexpressed during episodes of heart pressure overload, typically seen in hypertrophic cardiomyopathies.…”

Section: Enrichment Of Transcription Factor Binding Motifs In Putativ...mentioning

confidence: 91%

Computational analysis of congenital heart disease associated SNPs: Unveiling their impact on the gene regulatory system

Vashisht,

Parisi,

Winata

2024

Preprint

View full text Add to dashboard Cite

Background Congenital heart disease (CHD) is a prevalent condition characterized by defective heart development, causing premature death and stillbirths among infants. Genome-wide association studies (GWASs) have provided insights into the role of genetic variants in CHD pathogenesis through the identification of a comprehensive set of single-nucleotide polymorphisms (SNPs). Notably, 90–95% of these variants reside in the noncoding genome, complicating the understanding of their underlying mechanisms. Results In this study, we developed a systematic computational pipeline for the identification and analysis of CHD-associated SNPs spanning both coding and noncoding regions of the genome. Initially, we curated a thorough dataset of SNPs from GWAS-catalog and ClinVar database and filtered them based on CHD-related traits. Subsequently, these CHD-SNPs were annotated and categorized into noncoding and coding regions based on their location. To study the functional implications of noncoding CHD-SNPs, we cross-validated them with enhancer-specific histone modification marks from developing human heart across 9 Carnegie stages and identified potential cardiac enhancers. This approach led to the identification of 2,056 CHD-associated putative enhancers (CHD-enhancers), 38.9% of them overlapping with known enhancers catalogued in human enhancer disease database. We identified heart-related transcription factor binding sites within these CHD-enhancers, offering insights into the impact of SNPs on TF binding. Conservation analysis further revealed that many of these CHD-enhancers were highly conserved across vertebrates, suggesting their evolutionary significance. Utilizing heart-specific expression quantitative trait loci (eQTL) data, we further identified a subset of 63 CHD-SNPs with regulatory potential distributed across various cardiac tissues. Concurrently, coding CHD-SNPs were represented as a protein interaction network and its subsequent binding energy analysis focused on a pair of proteins within this network, pinpointed a deleterious coding CHD-SNP, rs770030288, located in C2 domain of MYBPC3 protein. Conclusions Overall, our findings demonstrate that SNPs have the potential to disrupt gene regulatory systems, either by affecting enhancer sequences or modulating protein-protein interactions, which can lead to abnormal developmental processes contributing to CHD pathogenesis.

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“…Furthermore, the Krüppel‐like factor (KLF) family of transcription factors serves as crucial regulators of cardiovascular diseases, 60 as evidenced by their indispensable role in the modulation of cardiac fibroblasts during the myocardial adaptive response to pressure overload. Specifically, KLF5 has been shown to partially influence the development of fibroblasts, 61 and its cardiac fibroblast‐specific deletion has been demonstrated to mitigate cardiac hypertrophy in a moderate‐intensity pressure overload model by Takeda et al 62 In the interim, KLF5 was negatively regulated by SMURF2, resulting in an impact on cell proliferation 63 .…”

Section: Cardiovascular Diseasesmentioning

confidence: 99%

The role of SMURFs in non‐cancerous diseases

et al. 2023

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The ubiquitin‐proteasome system is a crucial mechanism for regulating protein levels in cells, with substrate‐specific E3 ubiquitin ligases serving as an integral component of this system. Among these ligases are SMAD‐specific E3 ubiquitin‐protein ligase 1 (SMURF1) and SMAD‐specific E3 ubiquitin‐protein ligase 2 (SMURF2), which belong to the neural precursor cell‐expressed developmentally downregulated 4 (NEDD4) subfamily of Homologous to E6‐AP COOH terminus (HECT)‐type E3 ligases. As E3 ligases, SMURFs have critical functions in regulating the stability of multiple proteins, thereby maintaining physiological processes such as cell migration, proliferation, and apoptosis. The occurrence of many diseases is attributed to abnormal cell physiology and an imbalance in cell homeostasis. It is noteworthy that SMURFs play pivotal roles in disease progression, with the regulatory functions being complex and either facilitative or inhibitory. In this review, we elucidate the mechanisms by which SMURF1 and SMURF2 can regulate disease progression in non‐cancerous diseases. These significant findings offer potential novel therapeutic targets for various diseases and new avenues for research on SMURF proteins.

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The Involvement of Krüppel-like Factors in Cardiovascular Diseases

Cited by 15 publications

References 143 publications

Computational analysis of congenital heart disease associated SNPs: Unveiling their impact on the gene regulatory system

Computational analysis of congenital heart disease associated SNPs: Unveiling their impact on the gene regulatory system

Computational analysis of congenital heart disease associated SNPs: Unveiling their impact on the gene regulatory system

The role of SMURFs in non‐cancerous diseases

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