Circular Network of Coregulated Sphingolipids Dictates Chronic Hypoxia Damage in Patients With Tetralogy of Fallot

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Abstract

Background: Tetralogy of Fallot (TOF) is the most common cyanotic heart disease. However, the association of cardiac metabolic reprogramming changes and underlying molecular mechanisms in TOF-related chronic myocardial hypoxia damage are still unclear.

Methods: In this study, we combined microarray transcriptomics analysis with liquid chromatography tandem-mass spectrometry (LC–MS/MS) spectrum metabolomics analysis to establish the metabolic reprogramming that occurs in response to chronic hypoxia damage. Two Gene Expression Omnibus (GEO) datasets, GSE132176 and GSE141955, were downloaded to analyze the metabolic pathway in TOF. Then, a metabolomics analysis of the clinical samples (right atrial tissue and plasma) was performed. Additionally, an association analysis between differential metabolites and clinical phenotypes was performed. Next, four key genes related to sphingomyelin metabolism were screened and their expression was validated by real-time quantitative PCR (QT-PCR).

Results: The gene set enrichment analysis (GSEA) showed that sphingolipid metabolism was downregulated in TOF and the metabolomics analysis showed that multiple sphingolipids were dysregulated. Additionally, genes related to sphingomyelin metabolism were identified. We found that four core genes, UDP-Glucose Ceramide Glucosyltransferase ( UGCG), Sphingosine-1-Phosphate Phosphatase 2 ( SGPP2), Fatty Acid 2-Hydroxylase ( FA2H), and Sphingosine-1-Phosphate Phosphatase 1 ( SGPP1), were downregulated in TOF.

Conclusion: Sphingolipid metabolism was downregulated in TOF; however, the detailed mechanism needs further investigation.

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Most cited references 58

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clusterProfiler: an R package for comparing biological themes among gene clusters.

Guangchuang Yu, Li-Gen Wang, Yanyan Han … (2012)

Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis. Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters. The analysis module and visualization module were combined into a reusable workflow. Currently, clusterProfiler supports three species, including humans, mice, and yeast. Methods provided in this package can be easily extended to other species and ontologies. The clusterProfiler package is released under Artistic-2.0 License within Bioconductor project. The source code and vignette are freely available at http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html.

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limma powers differential expression analyses for RNA-sequencing and microarray studies

Matthew E. Ritchie, Belinda Phipson, Di Wu … (2015)

limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.

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KEGG: kyoto encyclopedia of genes and genomes.

M Kanehisa (2000)

KEGG (Kyoto Encyclopedia of Genes and Genomes) is a knowledge base for systematic analysis of gene functions, linking genomic information with higher order functional information. The genomic information is stored in the GENES database, which is a collection of gene catalogs for all the completely sequenced genomes and some partial genomes with up-to-date annotation of gene functions. The higher order functional information is stored in the PATHWAY database, which contains graphical representations of cellular processes, such as metabolism, membrane transport, signal transduction and cell cycle. The PATHWAY database is supplemented by a set of ortholog group tables for the information about conserved subpathways (pathway motifs), which are often encoded by positionally coupled genes on the chromosome and which are especially useful in predicting gene functions. A third database in KEGG is LIGAND for the information about chemical compounds, enzyme molecules and enzymatic reactions. KEGG provides Java graphics tools for browsing genome maps, comparing two genome maps and manipulating expression maps, as well as computational tools for sequence comparison, graph comparison and path computation. The KEGG databases are daily updated and made freely available (http://www. genome.ad.jp/kegg/).

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Author and article information

Contributors

Rongjun Zou: URI : http://loop.frontiersin.org/people/644622/overview

Guodong Huang: URI : http://loop.frontiersin.org/people/1338393/overview

Li Ma: URI : http://loop.frontiersin.org/people/1115759/overview

Xinxin Chen: URI : http://loop.frontiersin.org/people/1232759/overview

Journal

Journal ID (nlm-ta): Front Cardiovasc Med

Journal ID (iso-abbrev): Front Cardiovasc Med

Journal ID (publisher-id): Front. Cardiovasc. Med.

Title: Frontiers in Cardiovascular Medicine

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2297-055X

Publication date (Electronic): 13 January 2022

Publication date Collection: 2021

Volume: 8

Electronic Location Identifier: 780123

Affiliations

[1] ¹Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University , Guangzhou, China

[2] ²Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Department of Extracorporeal Circulation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University , Guangzhou, China

[3] ³Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou, China

Author notes

Edited by: Jian Zhuang, Guangdong Provincial People's Hospital, China

Reviewed by: Cheng Liu, Guangzhou First People's Hospital, China; Hao Zhou, University of Wyoming, United States

*Correspondence: Guodong Huang 13926665546@ 123456139.com

Li Ma limagz@ 123456163.com

Xinxin Chen xinxinchengz@ 123456163.com

This article was submitted to Pediatric Cardiology, a section of the journal Frontiers in Cardiovascular Medicine

†These authors have contributed equally to this work

Article

DOI: 10.3389/fcvm.2021.780123

PMC ID: 8792512

PubMed ID: 35097000

SO-VID: 9ff7997a-8daa-44fc-a190-2bddba1bf8b2

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 20 September 2021

Date accepted : 10 December 2021

Page count

Figures: 7, Tables: 1, Equations: 0, References: 58, Pages: 13, Words: 7346

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Circular Network of Coregulated Sphingolipids Dictates Chronic Hypoxia Damage in Patients With Tetralogy of Fallot

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Exponential Random Graph Models

Most cited references 58

clusterProfiler: an R package for comparing biological themes among gene clusters.

limma powers differential expression analyses for RNA-sequencing and microarray studies

KEGG: kyoto encyclopedia of genes and genomes.

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