Trisomy 21-driven metabolite alterations are linked to cellular injuries in Down syndrome.

Down syndrome (DS) arises from a genetic anomaly characterized by an extra copy of chromosome 21 (exCh21). Despite high incidence of congenital diseases among DS patients, direct impacts of exCh21 remain elusive. Here, we established a robust DS model harnessing human-induced pluripotent stem cells (hiPSCs) from mosaic DS patient. These hiPSC lines encompassed both those with standard karyotype and those carrying an extra copy of exCh21, allowing to generate isogenic cell lines with a consistent genetic background. We unraveled that exCh21 inflicted disruption upon the cellular transcriptome, ushering in alterations in metabolic processes and triggering DNA damage. The impact of exCh21 was also manifested in profound modifications in chromatin accessibility patterns. Moreover, we identified two signature metabolites, 5-oxo-ETE and Calcitriol, whose biosynthesis is affected by exCh21. Notably, supplementation with 5-oxo-ETE promoted DNA damage, in stark contrast to the protective effect elicited by Calcitriol against such damage. We also found that exCh21 disrupted cardiogenesis, and that this impairment could be mitigated through supplementation with Calcitriol. Specifically, the deleterious effects of 5-oxo-ETE unfolded in the form of DNA damage induction and the repression of cardiogenesis. On the other hand, Calcitriol emerged as a potent activator of its nuclear receptor VDR, fostering amplified binding to chromatin and subsequent facilitation of gene transcription. Our findings provide a comprehensive understanding of exCh21's metabolic implications within the context of Down syndrome, offering potential avenues for therapeutic interventions for Down syndrome treatment.

Atypical deletion of Williams-Beuren syndrome reveals the mechanism of neurodevelopmental disorders.

Genes associated with specific neurocognitive phenotypes in Williams-Beuren syndrome are still controversially discussed. This study identified nine patients with atypical deletions out of 111 patients with Williams-Beuren syndrome; these deletions included seven smaller deletions and two larger deletions. One patient had normal neurodevelopment with a deletion of genes on the distal side of the Williams-Beuren syndrome chromosomal region, including GTF2I and GTF2IRD1. However, another patient retained these genes but showed neurodevelopmental abnormalities. By comparing the genotypes and phenotypes of patients with typical and atypical deletions and previous reports in the literature, we hypothesize that the BAZ1B, FZD9, and STX1A genes may play an important role in the neurodevelopment of patients with WBS.

Multi-factor regulatory network and different clusters in hypertrophic obstructive cardiomyopathy.

BACKGROUND: Practical biosignatures and thorough understanding of regulatory processes of hypertrophic obstructive cardiomyopathy (HOCM) are still lacking. METHODS: Firstly, public data from GSE36961 and GSE89714 datasets of Gene Expression Omnibus (GEO), Gene database of NCBI (National Center of Biotechnology Information) and Online Mendelian Inheritance in Man (OMIM) database were merged into a candidate gene set of HOCM. Secondly, weighted gene co-expression network analysis (WGCNA) for the candidate gene set was carried out to determine premier co-expressed genes. Thirdly, significant regulators were found out by virtue of a multi-factor regulatory network of long non-coding RNAs (lncRNAs), messenger RNAs (mRNAs), microRNAs (miRNAs) and transcription factors (TFs) with molecule interreactions from starBase v2.0 database and TRRUST v2 database. Ultimately, HOCM unsupervised clustering and "tsne" dimensionality reduction was employed to gain hub genes, whose classification performance was evaluated by a multinomial model of lasso logistic regression analysis binded with receiver operating characteristic (ROC) curve. RESULTS: Two HOCM remarkably-interrelated modules were from WGCNA, followed by the recognition of 32 crucial co-expressed genes. The multi-factor regulatory network disclosed 7 primary regulatory agents, containing lncRNAs (XIST, MALAT1, and H19), TFs (SPI1 and SP1) and miRNAs (hsa-miR-29b-39 and has-miR-29a-3p). Four clusters of HOCM and 4 hub genes (COMP, FMOD, AEBP1 and SULF1) significantly expressing in preceding four subtypes were obtained, while ROC curve demonstrated satisfactory performance of clustering and 4 genes. CONCLUSIONS: Our consequences furnish valuable resource which may bring about prospective mechanistic and therapeutic anatomization in HOCM.

Asporin is a Potential Promising Biomarker for Common Heart Failure.

Heart failure (HF) is the end-stage of various diseases, especially ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). We aimed to investigate the common molecular mechanism of ICM and DCM. Differentially expressed genes (DEGs) of ICM or DCM samples compared with control were identified in GSE1869, GSE5406, GSE57338, GSE79962, GSE116250, and GSE46224 datasets. Functional enrichment analysis and protein-protein network analysis of the coregulated DEGs in at least four datasets were performed using the online tools of DAVID, the Metascape database, and the STRING database. Hub genes of HF were identified and validated by western blotting (WB) and immunohistochemistry in our tissue microarray (TMA). Seventy-four coregulated ICM and 126 coregulated DCM relevant DEGs were identified. Moreover, 59 common genes between ICM and DCM relevant DEGs were obtained, which were mainly involved in cardiac fibrosis and several signal pathways, such as Wnt signal pathway, PI3K-Akt signal pathway, and HIF-1A signal pathway. Among the six hub genes with top degrees, asporin (ASPN) had a relatively higher correlation with LVEF. Finally, TMA and WB results revealed that the ASPN protein was significantly increased in ICM and DCM left ventricular samples. The present study revealed some common molecular mechanisms of HF with different causes. Furthermore, ASPN may be a potential promising biomarker for HF.

FLNC and MYLK2 Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy.

Mutations in the sarcomeric protein filamin C (FLNC) gene have been linked to hypertrophic cardiomyopathy (HCM), as they have been determined to increase the risk of ventricular arrhythmia and sudden death. Thus, in this study, we identified a novel missense mutation of FLNC in a Chinese family with HCM, and, interestingly, a second novel truncating mutation of MYLK2 was discobered in one family member with different phenotype.We performed whole-exome sequencing in a Chinese family with HCM of unknown cause. To determine and confirm the function of a novel mutation of FLNC, we introduced the mutant and wild-type gene into AC16 cells (human cardiomyocytes): we then used western blotting to analyze the expression of FLNC in subcellular fractions, and confocal microscope to observe the subcellular distribution of the protein.As per our findings, we were able to identify a novel missense single nucleotide variant (FLNC c.G5935A [p.A1979T]) in the family, which segregates with the disease. FLNC expression levels were observed to be equivalent in both wild-type and p.A1979T cardiomyocytes. However, the expression of the mutant protein has resulted in cytoplasmic protein aggregations, in contrast to wild-type FLNC, which was distributed in the cytoplasm and did not form aggregates. Unexpectedly, a second truncating mutation, NM_033118:exon8:c.G1138T:p.E380X of the MYLK2 gene, was identified in the mother of the proband with dilated cardiomyopathy, which was not found in other subjects.We then identified the FLNC A1979T mutation as a novel pathogenic variant associated with HCM in a Chinese family as well as a second causal mutation in a family member with a distinct phenotype. The possibility that there is more than one causal mutation in cardiomyopathy warrants clinical attention, especially for patients with atypical clinical features.

Systematic analysis of molecular mechanisms of heart failure through the pathway and network-based approach.

AIMS: The molecular networks and pathways involved in heart failure (HF) are still largely unknown. The present study aimed to systematically investigate the genes associated with HF, comprehensively explore their interactions and functions, and identify possible regulatory networks involved in HF. MAIN METHODS: The weighted gene coexpression network analysis (WGCNA), crosstalk analysis, and Pivot analysis were used to identify gene connections, interaction networks, and molecular regulatory mechanisms. Functional analysis and protein-protein interaction (PPI) were performed using DAVID and STRING databases. Gene set variation analysis (GSVA) and receiver operating characteristic (ROC) curve analysis were also performed to evaluate the relationship of the hub genes with HF. KEY FINDINGS: A total of 5968 HF-related genes were obtained to construct the co-expression networks, and 18 relatively independent and closely linked modules were identified. Pivot analysis suggested that four transcription factors and five noncoding RNAs were involved in regulating the process of HF. The genes in the module with the highest positive correlation to HF was mainly enriched in cardiac remodeling and response to stress. Five upregulated hub genes (ASPN, FMOD, NT5E, LUM, and OGN) were identified and validated. Furthermore, the GSVA scores of the five hub genes for HF had a relatively high areas under the curve (AUC). SIGNIFICANCE: The results of this study revealed specific molecular networks and their potential regulatory mechanisms involved in HF. These may provide new insight into understanding the mechanisms underlying HF and help to identify more effective therapeutic targets for HF.

PGAM1 deficiency ameliorates myocardial infarction remodeling by targeting TGF-ß via the suppression of inflammation, apoptosis and fibrosis.

Myocardial ischemia-reperfusion (MIR) represents critical challenge for the treatment of acute myocardial infarction diseases. Presently, identifying the molecular basis revealing MIR progression is scientifically essential and may provide effective therapeutic strategies. Phosphoglycerate mutase 1 (PGAM1) is a key aerobic glycolysis enzyme, and exhibits critical role in mediating several biological events, such as energy production and inflammation. However, whether PGAM1 can affect MIR is unknown. Here we showed that PGAM1 levels were increased in murine ischemic hearts. Mice with cardiac knockout of PGAM1 were resistant to MIR-induced heart injury, evidenced by the markedly reduced infarct volume, improved cardiac function and histological alterations in cardiac sections. In addition, inflammatory response, apoptosis and fibrosis in hearts of mice with MIR operation were significantly alleviated by the cardiac deletion of PGAM1. Mechanistically, the activation of nuclear transcription factor κB (NF-κB), p38, c-Jun NH2-terminal kinase (JNK) and transforming growth factor ß (TGF-ß) signaling pathways were effectively abrogated in MI-operated mice with specific knockout of PGAM1 in hearts. The potential of PGAM1 suppression to inhibit inflammatory response, apoptosis and fibrosis were verified in the isolated cardiomyocytes and fibroblasts treated with oxygen-glucose deprivation reperfusion (OGDR) and TGF-ß, respectively. Importantly, PGAM1 directly interacted with TGF-ß to subsequently mediate inflammation, apoptosis and collagen accumulation, thereby achieving its anti-MIR action. Collectively, these findings demonstrated that PGAM1 was a positive regulator of myocardial infarction remodeling due to its promotional modulation of TGF-ß signaling, indicating that PGAM1 may be a promising therapeutic target for MIR treatment.

Global gene expression analysis using RNA-seq reveals the new roles of Panax notoginseng Saponins in ischemic cardiomyocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng saponins (PNS), the main active ingredients of Panax notoginseng (Burkill) F.H.Chen, have been clinically used for cardiovascular diseases treatment in China as the Traditional Chinese Medicine (TCM) (Duan et al., 2017). Evidence demonstrated that PNS protected cardiomyocytes from myocardial ischemia, but the more underlying molecular mechanisms of the protective effect are still unclear. The aims of this study are to systematically know the function of PNS and discover new roles of PNS in ischemic cardiomyocytes. MATERIALS AND METHODS: To confirm PNS function on ischemic cardiomyopathy, we established in vitro myocardial ischemia model on H9C2 cardiomyocyte line, which was induced by oxygen-glucose depletion (OGD). Then RNA-seq was carried out to systematically analyze global gene expression. This study was aimed to systematically investigate the protective effect and more potential molecular mechanisms of PNS on H9C2 cardiomyocytes in vitro through whole-transcriptome analysis with total RNA sequencing (RNA-Seq). RESULTS: PNS exhibited anti-apoptotic effect in H9C2 cardiomyocytes in OGD-induced myocardial ischemia model. Through RNA-seq, we found that OGD affected expression profiling of many genes, including upregulated and downregulated genes. PNS inhibited cardiomyocyte apoptosis and death through rescuing cell cycle arrest, the DNA double-strand breakage repair process and chromosome segregation. Interestingly, for the canonical signaling pathways regulation, RNA-seq showed PNS could inhibit cardiac hypertrophy, MAPK signaling pathway, and re-activate PI3K/AKT and AMPK signaling pathways. Experimental data also confirmed the PNS could protect cardiomyocytes from OGD-induced apoptosis through activating PI3K/AKT and AMPK signaling pathways. Moreover, RNA-seq demonstrated that the expression levels of many non-coding RNAs, such as miRNAs and lncRNAs, were significantly affected after PNS treatment, suggesting that PNS could protect cardiomyocytes through regulating non-coding RNAs. CONCLUSION: RNA-seq systematically revealed different novel roles of Panax Notoginseng Saponins (PNS) in protecting cardiomyocytes from apoptosis, induced by myocardial ischemia, through rescuing cell cycle arrest and cardiac hypertrophy, re-activating the DNA double-strand breakage repair process, chromosome segregation, PI3K/Akt and AMPK signaling pathways and regulating non-coding RNAs.

Analysis of genes and underlying mechanisms involved in foam cells formation and atherosclerosis development.

BACKGROUND: Foam cells (FCs) play crucial roles in the process of all stages of atherosclerosis. Smooth muscle cells (SMCs) and macrophages are the major sources of FCs. This study aimed to identify the common molecular mechanism in these two types of FCs. METHODS: GSE28829, GSE43292, GSE68021, and GSE54666 were included to identify the differentially expressed genes (DEGs) associated with FCs derived from SMCs and macrophages. Gene Ontology biological process (GO-BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by using the DAVID database. The co-regulated genes associated with the two origins of FCs were validated (GSE9874), and their expression in vulnerable atherosclerosis plaques (GSE120521 and GSE41571) was assessed. RESULTS: A total of 432 genes associated with FCs derived from SMCs (SMC-FCs) and 81 genes associated with FCs derived from macrophages (M-FCs) were identified, and they were mainly involved in lipid metabolism, inflammation, cell cycle/apoptosis. Furthermore, three co-regulated genes associated with FCs were identified: GLRX, RNF13, and ABCA1. These three common genes showed an increased tendency in unstable or ruptured plaques, although in some cases, no statistically significant difference was found. CONCLUSIONS: DEGs related to FCs derived from SMCs and macrophages have contributed to the understanding of the molecular mechanism underlying the formation of FCs and atherosclerosis. GLRX, RNF13, and ABCA1 might be potential targets for atherosclerosis treatment.