Wnt11 regulates cardiac chamber development and disease during perinatal maturation

Touma, Marlin; Kang, Xuedong; Gao, Fuying; Zhao, Yan; Cass, Ashley; Biniwale, Reshma; Xiao, Xinshu; Eghbali, Mansuoreh; Coppola, Giovanni; Reemtsen, Brian; Wang, Yibin

doi:10.1172/jci.insight.94904

Cited by 26 publications

(31 citation statements)

References 51 publications

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“…and performed paired-end RNA-seq as we previously described [23,24]. Out of the three candidate genes, ALMS1 was the only gene expressed in dermal broblasts with good read coverage as illustrated by IGV viewer, while neither DNAH8 nor DNAH17 was detected.…”

Section: Resultsmentioning

confidence: 99%

“…We systematically analyzed pEFE dermal broblast-derived RNA-seq datasets using total RNA obtained from three independent biological replicates. In addition, three independent hNDF replicates were subjected to the same RNA-seq protocol as we previously described [23,24].…”

Section: Resultsmentioning

confidence: 99%

“…RNA Sequencing and Bioinformatics Analysis: RNA sequencing, data processing, and bioinformatics analysis steps follow exactly the procedures we previously described [23,24]. Brie y, total RNAs were isolated, ribosomal RNAs were depleted (RiboZero Gold, Illumina), and the resulting RNA transcripts were processed into short fragments (about 200~500nt).…”

Section: Methodsmentioning

confidence: 99%

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Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations in Primary Endocardial Fibroelastosis: a Rare Neonatal Cardiomyopathy

Zhao

Wang

Eskin

et al. 2021

Preprint

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Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy with a devastating course and grave prognosis. To investigate the potential genetic cause that underlies pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1938delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband’s dermal fibroblasts confirmed the impact of novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFβ signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations in Primary Endocardial Fibroelastosis: a Rare Neonatal Cardiomyopathy

Zhao

Wang

Eskin

et al. 2021

Preprint

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“…The GO and pathway enrichment analysis of DEG are closely related to obesity associated type 2 diabetes mellitus genes and advancement. KCNE5 [45], SHANK3 [46], CASQ2 [47], EDNRA (endothelin receptor type A) [48], EPHB4 [49], ALPK3 [50], WNT11 [51], IRAK2 [52], FBN1 [53], SFRP2 [54], CLCA2 [55], NEXN (nexilin F-actin binding protein) [56], PALLD (palladin, cytoskeletal associated protein) [57], DAB2 [58], NRP2 [59], THBS2 [60], CSF1R [61], KCNA2 [62], CACNA1C [63], F2R [64], UCHL1 [65], CCL18 [66], ITGB1BP2 [67] and FMOD ( bromodulin) [68] were reportedly involved in cardio vascular diseases, but these genes might be key for progression of obesity associated type 2 diabetes mellitus. Hu et al [69], Liu et al [70], Eltokhi et al [71], Cai et al [72], Pfeiffer et al [73], Lin et al [74], Royer-Zemmour et al [75], Pastor et al [76], Goodspeed et al [77], Zhang et al [78], Rogers et al [79], Su et al [80] and Foale et al [81] reported that NRXN1, CRHR1, SHANK2, PSEN2, CKB (creatine kinase B), CD200R1, SRPX2, PTPRZ1, SLC6A1, GABRB2, KCNA1, ASAH1 and LINGO1 were linked with progression of neuropsychiatric disorders, but these genes might be involved in advancement of obesity associated type 2 diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules 

Prashanth

Vastrad²,

Tengli

et al. 2020

Preprint

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BackgroundObesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the development mechanism of obesity associated type 2 diabetes mellitus. MethodsTo screen the differentially expressed genes (DEGs) that may play essential roles in obesity associated type 2 diabetes mellitus, the public expression profiling by high throughput sequencing data (GSE143319) were downloaded and screened for DEGs. Then, Gene Ontology (GO) function analysis and REACTOME pathway analysis were performed. To screen hub and target genes, the protein–protein interaction network, miRNA-target genes regulatory network and TF-target gene regulatory network were constructed. The Receiver operating characteristic (ROC) curve analysis and RT- PCR analysis of hub genes in obesity associated type 2 diabetes mellitus were also analyzed. Final molecular docking studies performed for screening small drug molecules. ResultsThere were 409 up regulated and 411 down regulated genes detected, and the biological processes of the GO analysis were enriched in regulation of ion transmembrane transport, intrinsic component of plasma membrane, transferase activity, transferring phosphorus-containing groups, cell adhesion, integral component of plasma membrane and signaling receptor binding, whereas, the REACTOME pathway analysis was enriched in integration of energy metabolism and extracellular matrix organization. The hub genes CEBPD, TP73, ESR2, TAB1, MAP3K5, FN1, UBD, RUNX1, PIK3R2 and TNF, which might play a essential role in obesity associated type 2 diabetes mellitus was further screened. ConclusionsThe present study could deepen the understanding of the molecular mechanism of obesity associated type 2 diabetes mellitus, which could be useful in developing clinical treatments of obesity associated type 2 diabetes mellitus.

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“…67 , 68 A chamber-specific transcriptome analysis in neonatal mice at postnatal days 0, 3, and 7 better defined the mechanisms by which Wnt signaling drives chamber differentiation. 69 Although many expression patterns were shared (eg, the switch from carbohydrate to fatty acid metabolism), some differed in magnitude and kinetics, particularly at postnatal day 3. Genes involved in the polo-like kinase mitotic pathway ( plk1 [polo-like kinase], ccnb1 [cyclin B1], ccnb2 , and cdc25c ) were abruptly suppressed in the RV at day 3, but their suppression in the LV was much more gradual.…”

Section: Differences Between the Rv And LVmentioning

confidence: 99%

Stem Cell Therapy for Hypoplastic Left Heart Syndrome

Bittle

Morales

Deatrick

et al. 2018

Circulation Research

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Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease.

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Wnt11 regulates cardiac chamber development and disease during perinatal maturation

Cited by 26 publications

References 51 publications

Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations in Primary Endocardial Fibroelastosis: a Rare Neonatal Cardiomyopathy

Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations in Primary Endocardial Fibroelastosis: a Rare Neonatal Cardiomyopathy

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules

Stem Cell Therapy for Hypoplastic Left Heart Syndrome

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Wnt11 regulates cardiac chamber development and disease during perinatal maturation

Cited by 26 publications

References 51 publications

Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations in Primary Endocardial Fibroelastosis: a Rare Neonatal Cardiomyopathy

Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations in Primary Endocardial Fibroelastosis: a Rare Neonatal Cardiomyopathy

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules&nbsp;

Stem Cell Therapy for Hypoplastic Left Heart Syndrome

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Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules