Pseudogenes in Cardiovascular Disease

Qi, Yanyan; Wang, Xi; Li, Wenbo; Chen, Dongchang; An, Shengli

doi:10.3389/fmolb.2020.622540

Cited by 10 publications

(5 citation statements)

References 87 publications

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“…Pioneering works have rehabilitated a processed Adh gene (jingwei) as a functional copy [11,12], instead of a defective pseudogene as previously reported. With the availability of high-throughput sequencing recently, a growing body of evidence has uncovered the functions of some pseudogenes under physiological and pathological conditions [13][14][15][16][17][18]. For example, some studies showed that pseudogenes played important roles in cancer progression and could stratify the subtype of kidney cancer [19,20].…”

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confidence: 99%

Evolution and function of developmentally dynamic pseudogenes in mammals

et al. 2022

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Background Pseudogenes are excellent markers for genome evolution, which are emerging as crucial regulators of development and disease, especially cancer. However, systematic functional characterization and evolution of pseudogenes remain largely unexplored. Results To systematically characterize pseudogenes, we date the origin of human and mouse pseudogenes across vertebrates and observe a burst of pseudogene gain in these two lineages. Based on a hybrid sequencing dataset combining full-length PacBio sequencing, sample-matched Illumina sequencing, and public time-course transcriptome data, we observe that abundant mammalian pseudogenes could be transcribed, which contribute to the establishment of organ identity. Our analyses reveal that developmentally dynamic pseudogenes are evolutionarily conserved and show an increasing weight during development. Besides, they are involved in complex transcriptional and post-transcriptional modulation, exhibiting the signatures of functional enrichment. Coding potential evaluation suggests that 19% of human pseudogenes could be translated, thus serving as a new way for protein innovation. Moreover, pseudogenes carry disease-associated SNPs and conduce to cancer transcriptome perturbation. Conclusions Our discovery reveals an unexpectedly high abundance of mammalian pseudogenes that can be transcribed and translated, and these pseudogenes represent a novel regulatory layer. Our study also prioritizes developmentally dynamic pseudogenes with signatures of functional enrichment and provides a hybrid sequencing dataset for further unraveling their biological mechanisms in organ development and carcinogenesis in the future.

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confidence: 99%

Evolution and function of developmentally dynamic pseudogenes in mammals

et al. 2022

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“…However, recent studies have shown that pseudogenes may play important roles in CVDs. 42 Elevated low-density lipoprotein cholesterol (LDL-C) level is a main risk factor for CVDs, while knockdown of zinc finger protein 542 pseudogene (ZNF542P) increases the LDL-C level response to simvastatin in a human hepatoma cell line. 43 The mRNA levels of octamer-binding transcription factor 4 (Oct 4) pseudogene Oct-4-psG1 and Oct-4-psG5 are significantly down-regulated in pulmonary arterial smooth muscle cells (PASMC) in patients with idiopathic pulmonary arterial hypertension (IPAH), indicating that Oct-4-psG1 and Oct-4-psG5 are involved in IPAH.…”

Section: Discussionmentioning

confidence: 99%

CVD-associated SNPs with regulatory potential drive pathologic non-coding RNA expression

Zhu

Baumgarten

et al. 2023

Preprint

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Background: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) appearing in non-coding genomic regions in CVDs. The SNPs may alter gene expression by modifying transcription factor (TF) binding sites and lead to functional consequences in cardiovascular traits or diseases. To understand the underlying molecular mechanisms, it is crucial to identify which variations are involved and how they affect TF binding. Methods: The SNEEP (SNP exploration and analysis using epigenomics data) pipeline was used to identify regulatory SNPs, which alter the binding behavior of TFs and link GWAS SNPs to their potential target genes for six CVDs. The human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs), monoculture cardiac organoids (MCOs) and self-organized cardiac organoids (SCOs) were used in the study. Gene expression, cardiomyocyte size and cardiac contractility were assessed. Results: By using our integrative computational pipeline, we identified 1905 regulatory SNPs in CVD GWAS data. These were associated with hundreds of genes, half of them non-coding RNAs (ncRNAs), suggesting novel CVD genes. We experimentally tested 40 CVD-associated non- coding RNAs, among them RP11-98F14.11, RPL23AP92, IGBP1P1, and CTD-2383I20.1, which were upregulated in hiPSC-CMs, MCOs and SCOs under hypoxic conditions. Further experiments showed that IGBP1P1 depletion rescued expression of hypertrophic marker genes, reduced hypoxia-induced cardiomyocyte size and improved hypoxia-reduced cardiac contractility in hiPSC-CMs and MCOs. Conclusions: IGBP1P1 is a novel ncRNA with key regulatory functions in modulating cardiomyocyte size and cardiac function in our disease models. Our data suggest ncRNA IGBP1P1 as a potential therapeutic target to improve cardiac function in CVDs.

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“…Pseudogenes are defined as regions of the genome that contain defective copies of genes and are often considered as nonfunctional ncRNA. However, recent studies have shown that pseudogenes may play important roles in CVDs [ 49 ]. Elevated low-density lipoprotein cholesterol (LDL-C) level is a main risk factor for CVDs, while knockdown of zinc finger protein 542 pseudogene (ZNF542P) increases the LDL-C level response to simvastatin in a human hepatoma cell line [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

CVD-associated SNPs with regulatory potential reveal novel non-coding disease genes

Zhu¹,

Baumgarten²,

Wu³

et al. 2023

Hum Genomics

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Background Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) appearing in non-coding genomic regions in CVDs. The SNPs may alter gene expression by modifying transcription factor (TF) binding sites and lead to functional consequences in cardiovascular traits or diseases. To understand the underlying molecular mechanisms, it is crucial to identify which variations are involved and how they affect TF binding. Methods The SNEEP (SNP exploration and analysis using epigenomics data) pipeline was used to identify regulatory SNPs, which alter the binding behavior of TFs and link GWAS SNPs to their potential target genes for six CVDs. The human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs), monoculture cardiac organoids (MCOs) and self-organized cardiac organoids (SCOs) were used in the study. Gene expression, cardiomyocyte size and cardiac contractility were assessed. Results By using our integrative computational pipeline, we identified 1905 regulatory SNPs in CVD GWAS data. These were associated with hundreds of genes, half of them non-coding RNAs (ncRNAs), suggesting novel CVD genes. We experimentally tested 40 CVD-associated non-coding RNAs, among them RP11-98F14.11, RPL23AP92, IGBP1P1, and CTD-2383I20.1, which were upregulated in hiPSC-CMs, MCOs and SCOs under hypoxic conditions. Further experiments showed that IGBP1P1 depletion rescued expression of hypertrophic marker genes, reduced hypoxia-induced cardiomyocyte size and improved hypoxia-reduced cardiac contractility in hiPSC-CMs and MCOs. Conclusions IGBP1P1 is a novel ncRNA with key regulatory functions in modulating cardiomyocyte size and cardiac function in our disease models. Our data suggest ncRNA IGBP1P1 as a potential therapeutic target to improve cardiac function in CVDs.

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Pseudogenes in Cardiovascular Disease

Cited by 10 publications

References 87 publications

Evolution and function of developmentally dynamic pseudogenes in mammals

Evolution and function of developmentally dynamic pseudogenes in mammals

CVD-associated SNPs with regulatory potential drive pathologic non-coding RNA expression

CVD-associated SNPs with regulatory potential reveal novel non-coding disease genes

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