Epigenetic regulation of insulin-like growth factor signaling: A novel insight into the pathophysiology of neonatal pulmonary hypertension

Madonna, Rosalinda; Caterina, Raffaele De; Geng, Yong

doi:10.1016/j.vph.2015.08.002

Cited by 11 publications

(5 citation statements)

References 22 publications

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“…SMAD6 is connected to endothelin 1 ( EDN1 ) and GZMA . COL1A1 , IGF1 , and EDN1 have all been associated with the pathophysiology of PAH ( Ooi et al, 2010 ; Pullamsetti et al, 2014 ; Madonna et al, 2015 ; McLaughlin et al, 2015 ), supporting our hypothesis that CCDC80 , SMAD6 , and GZMA may be involved in the disease pathophysiology.…”

Section: Resultssupporting

confidence: 83%

Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension

et al. 2016

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Pulmonary arterial hypertension (PAH) is a heterogeneous disorder associated with a progressive increase in pulmonary artery resistance and pressure. Although various therapies have been developed, the 5-year survival rate of PAH patients remains low. There is thus an important need to identify novel genes that are commonly dysregulated in PAH of various etiologies and could be used as biomarkers and/or therapeutic targets. In this study, we performed comparative transcriptome analysis of five mammalian PAH datasets downloaded from a public database. We identified 228 differentially expressed genes (DEGs) from a rat PAH model caused by inhibition of vascular endothelial growth factor receptor under hypoxic conditions, 379 DEGs from a mouse PAH model associated with systemic sclerosis, 850 DEGs from a mouse PAH model associated with schistosomiasis, 1598 DEGs from one cohort of human PAH patients, and 4260 DEGs from a second cohort of human PAH patients. Gene-by-gene comparison identified four genes that were differentially upregulated or downregulated in parallel in all five sets of DEGs. Expression of coiled-coil domain containing 80 (CCDC80) and anterior gradient two genes was significantly increased in the five datasets, whereas expression of SMAD family member six and granzyme A was significantly decreased. Weighted gene co-expression network analysis revealed a connection between CCDC80 and collagen type I alpha 1 (COL1A1) expression. To validate the function of CCDC80 in vivo, we knocked out ccdc80 in zebrafish using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. In vivo imaging of zebrafish expressing a fluorescent protein in endothelial cells showed that ccdc80 deletion significantly increased the diameter of the ventral artery, a vessel supplying blood to the gills. We also demonstrated that expression of col1a1 and endothelin-1 mRNA was significantly decreased in the ccdc80-knockout zebrafish. Finally, we examined Ccdc80 immunoreactivity in a rat PAHmodel and found increased expression in the hypertrophied media and adventitia of the pre-acinar pulmonary arteries (PAs) and in the thickened intima, media, and adventitia of the obstructed intra-acinar PAs. These results suggest that increased expression of CCDC80 may be involved in the pathogenesis of PAH, potentially by modulating the expression of endothelin-1 and COL1A1.

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Section: Resultssupporting

confidence: 83%

Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension

et al. 2016

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“…Epigenetic modulation is one of the important mechanisms of environmental factors regulating tumorigenesis 25 . Epigenetic changes might be caused by these environmental factors including hypoxia, inflammation, free radicals 31 . As a systemic environmental factor, hyperinsulinemia has been reported to regulate several genes methylation status 32 .…”

Section: Discussionmentioning

confidence: 99%

Increased TET1 Expression in Inflammatory Microenvironment of Hyperinsulinemia Enhances the Response of Endometrial Cancer to Estrogen by Epigenetic Modulation of GPER

Xie

Yang

et al. 2017

J. Cancer

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Background: Insulin resistance (IR) has been well studied in the initiation and development of endometrial endometrioid carcinoma (EEC). As yet, it has been largely neglected for estrogen sensitivity in local endometrium in hyperinsulinemia-induced systemic microenvironment. The aim of this study was to investigate the role of insulin in regulating estrogen sensitivity and explore the potential mechanisms in insulin-driven inflammatory microenvironment.Methods: We first investigated the effect of insulin on estradiol-driven endometrial cancer cells proliferation in vitro to address the roles of insulin in modulating estrogen sensitivity. Then GPER, ERα and TET1 in EEC samples with or without insulin resistance were screened by immunohistochemistry to confirm whether insulin resistance regulates estrogen receptors. Further mechanism analysis was carried out to address whether TET1 was mediated epigenetic modulation of GPER in insulin-induced microenvironment.Results: Insulin enhanced estradiol-driven endometrial cancer cells proliferation by up-regulating G-protein-coupled estrogen receptor (GPER) expression, but not ERα or ERβ. Immunohistochemistry of EEC tissues showed that GPER expression was greatly increased in endometrial tissues from EEC subjects with insulin resistance and was positively correlated with Ten-eleven-translocation 1 (TET1) expression. Mechanistically, insulin up-regulates TET1 expression, and the latter, an important DNA hydroxymethylase, could up-regulate GPER expression through epigenetic modulation.Conclusion: This study identified TET1 as the upstream regulator of GPER expression and provides a possible mechanism that insulin-induced positive regulation of estrogen sensitivity in endometrial cancer cells. Increasing expression of GPER through TET1-mediated epigenetic modulation may emerge as the main regulator to enhance the response of endometrial cancer to estrogen in insulin-driven inflammatory microenvironment.

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“…IGF1 plays a vital role in activating the Akt signalling pathway, a potent stimulator for cell proliferation and growth [ 15 ]. We therefore hypothesise that ASXL3 potentially has a role in transcriptional activation of IGF1 involved in this pathway potentially via epigenetic mechanisms [ 16 ], which could be contributing to short stature encountered in these patients.…”

Section: Discussionmentioning

confidence: 99%

Novel compound heterozygous ASXL3 mutation causing Bainbridge-ropers like syndrome and primary IGF1 deficiency

Giri

Rigden

Didi

et al. 2017

Int J Pediatr Endocrinol

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BackgroundDe novo truncating and splicing mutations in the additional sex combs-like 3 (ASXL3) gene have been implicated in the development of Bainbridge-Ropers syndrome (BRPS) characterised by severe developmental delay, feeding problems, short stature and characteristic facial features.Case presentationWe describe, for the first time, a patient with severe short stature, learning difficulties, feeding difficulties and dysmorphic features with a novel compound heterozygous mutation in ASXL3.Additionally the patient also has primary insulin like growth factor-1 (IGF1) deficiency. The mutations occur in exon 11 and proximal part of exon 12 and are strongly conserved at the protein level across various species. In-silico analyses using PolyPhen-2 and SIFT predict the amino acid substitutions to be potentially deleterious to the protein function. Detailed bioinformatics analysis show that the molecular defects caused by the two compound heterozygous mutations synergistically impact on two points of the molecular interaction network of ASXL3. ConclusionWe hypothesise that ASXL3 potentially has a role in transcriptional activation of IGF1 involved in signalling pathways that regulate cell proliferation and growth, which could be contributing to short stature encountered in these patients.

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Epigenetic regulation of insulin-like growth factor signaling: A novel insight into the pathophysiology of neonatal pulmonary hypertension

Cited by 11 publications

References 22 publications

Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension

Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension

Increased TET1 Expression in Inflammatory Microenvironment of Hyperinsulinemia Enhances the Response of Endometrial Cancer to Estrogen by Epigenetic Modulation of GPER

Novel compound heterozygous ASXL3 mutation causing Bainbridge-ropers like syndrome and primary IGF1 deficiency

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