The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression

Kelloniemi, Annina; Szabò, Zoltán; Serpi, Raisa; Näpänkangas, Juha; Ohukainen, Pauli; Tenhunen, Olli; Kaikkonen, Leena; Koivisto, Elina; Bagyura, Zsolt; Kerkelä, Risto; Léosdottír, Margret; Hedner, Thomas; Melander, Olle; Ruskoaho, Heikki; Rysä, Jaana

doi:10.1371/journal.pone.0130502

Cited by 20 publications

(16 citation statements)

References 55 publications

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“…We further ranked the KDs based on additional layers of data-rich analyses to provide high-confidence candidate genes for CAD. Our analyses not only detected well-implicated CAD disease genes such as lipid genes, COL4A2 , and CXCL12 34–36 but also unraveled novel key regulators for CAD such as LUM , HGD , F2 , ANXA3 , and STAT3 .…”

Section: Discussionmentioning

confidence: 70%

Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci

Zhao

Chen

Freudenberg

et al. 2016

ATVB

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Objective Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations. Approach and Results We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls. The networks and top-ranked regulators according to these data-driven criteria were further queried against literature, experimental evidence, and drug information to evaluate their disease relevance and potential as drug targets. Our analysis uncovered several potential novel regulators of CAD such as LUM and STAT3, which possess properties suitable as drug targets. We also revealed molecular relations and potential mechanisms through which the top CAD loci operate. Furthermore, we found that multiple CAD-relevant biological processes such as extracellular matrix, inflammatory and immune pathways, complement and coagulation cascades, and lipid metabolism interact in the CAD networks. Conclusions Our data-driven integrative genomics framework unraveled tissue-specific relations among the candidate genes of the CAD genome-wide association studies loci and prioritized novel network regulatory genes orchestrating biological processes relevant to CAD.

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Section: Discussionmentioning

confidence: 70%

Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci

Zhao

Chen

Freudenberg

et al. 2016

ATVB

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“…37 In rats, PHACTR1 is also down-regulated following myocardial infarction and may play a role in regulating the relative expression of actin isoforms in the heart. 38 ddPCR™ was used to confirm the differential expression of these transcripts (Figure 3A–E). …”

Section: Resultsmentioning

confidence: 99%

The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle

Saddic¹,

Sigurdsson²,

Chang³

et al. 2017

Circ Cardiovasc Genet

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Background The discovery of functional classes of long noncoding RNAs (lncRNAs) has expanded our understanding of the variety of RNA species that exist in cells. In the heart, lncRNAs have been implicated in the regulation of development, ischemic and dilated cardiomyopathy, and myocardial infarction. Nevertheless, there is a limited description of expression profiles for these transcripts in human subjects. Methods and Results We obtained left ventricular tissue from human patients undergoing cardiac surgery and used RNA sequencing to describe a lncRNA profile. We then identified a list of lncRNAs that were differentially expressed between pairs of samples before and after the ischemic insult of cardiopulmonary bypass. The expression of some of these lncRNAs correlates with ischemic time. Coding genes in close proximity to differentially expressed lncRNAs as well as coding genes that have coordinated expression with these lncRNAs are enriched in functional categories related to myocardial infarction including: heart function, metabolism, the stress response, and the immune system. Conclusions We describe a list of lncRNAs that are differentially expressed after ischemia in the human heart. These genes are predicted to function in pathways consistent with myocardial injury. As a result, lncRNAs may serve as novel diagnostic and therapeutic targets for ischemic heart disease. Clinical Trial Registration https://clinicaltrials.gov/; Unique Identifier: NCT00985049.

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“…Experimental studies revealed a pivotal role in vascular tube formation and actin polymerization [40•, 41•] Upregulation of PHACTR1 by TGFβ has been described [42•], potentially pointing to a connection with the TGFβ signaling pathway. A role in mechanotransduction has also been suggested [67]. …”

Section: Role Of Genetic Risk Factors In Common Multifactorial Strokementioning

confidence: 99%

Genetic Risk Factors for Ischemic and Hemorrhagic Stroke

2016

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Understanding the genetic risk factors for stroke is an essential step to decipher the underlying mechanisms, facilitate the identification of novel therapeutic targets, and optimize the design of prevention strategies. A very small proportion of strokes are attributable to monogenic conditions, the vast majority being multifactorial, with multiple genetic and environmental risk factors of small effect size. Genome-wide association studies and large international consortia have been instrumental in finding genetic risk factors for stroke. While initial studies identified risk loci for specific stroke subtypes, more recent studies also revealed loci associated with all stroke and all ischemic stroke. Risk loci for ischemic stroke and its subtypes have been implicated in atrial fibrillation (PITX2 and ZFHX3), coronary artery disease (ABO, chr9p21, HDAC9, and ALDH2), blood pressure (ALDH2 and HDAC9), pericyte and smooth muscle cell development (FOXF2), coagulation (HABP2), carotid plaque formation (MMP12), and neuro-inflammation (TSPAN2). For hemorrhagic stroke, two loci (APOE and PMF1) have been identified.

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The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression

Cited by 20 publications

References 55 publications

Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci

Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci

The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle

Genetic Risk Factors for Ischemic and Hemorrhagic Stroke

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