Molecular Genetics and Functional Analysis Implicate CDKN2BAS1-CDKN2B Involvement in POAG Pathogenesis

Rathi, Sonika; Danford, Ian; Gudiseva, Harini V.; Verkuil, Lana D.; Pistilli, Maxwell; Vishwakarma, Sushma; Kaur, Inderjeet; Dave, Tarjani Vivek; O’Brien, Joan M.; Chavali, Venkata R M

doi:10.3390/cells9091934

Cited by 15 publications

(17 citation statements)

References 54 publications

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“…CDKN2B encodes a cyclin-dependent kinase inhibitor, p15INK4b, which plays an important role in the regulation of the cell cycle through the inhibition of cyclin-dependent kinase 4 (CDK4) 43 . The expression of CDKN2B is significantly induced by TGF-β and plays a role in the mediation of TGF-β-induced cell cycle arrest 43,44,45 . TGF-β inhibits cell proliferation by producing G1 phase cell cycle arrest and CDKN2B, which forms a complex with either CDK4 or CDK6 preventing their activation, acts as an effector of TGF-β cell cycle arrest 46 .…”

Section: Discussionmentioning

confidence: 99%

“…CDKN2B was amongst the common TGF-β2 stimulated DEGs in the previous microarray studies 23,24,47 and in this RNA-Seq dataset. The upregulation of CDKN2B and CDKN2B-AS1 in human HTM cells is associated with senescence 45 and interestingly there is a decline in the HTM cell population with age and this decline is accelerated in POAG 48,49 . The underlying mechanisms of HTM cell loss with age and POAG have not been fully resolved and the interplay between TGF-β and HTM senescence needs further investigation 45,50,41,52. Unsurprisingly, several of the DEGs induced by TGF-β2 in the HTM have been implicated in the regulation of TGF-β2 signalling.…”

Section: Discussionmentioning

confidence: 99%

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Genome-Wide Transcriptome Profiling of Human Trabecular Meshwork Cells Treated with TGF-β2.

Willoughby

Lester

Whysall

et al. 2021

Preprint

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Glaucoma is a complex neurodegenerative disease resulting in progressive optic neuropathy and is a leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the predominant form affecting 65.5 million people globally. Despite the prevalence of POAG and the identification of over 120 glaucoma related genetic loci, the underlaying molecular mechanisms are still poorly understood. The transforming growth factor beta (TGF-β) signalling pathway is implicated in the molecular pathology of POAG. To gain a better understanding of the role TGF-β2 plays in the glaucomatous changes to the molecular pathology in the trabecular meshwork, we employed RNA-Seq to delineate the TGF-β2 induced changes in the transcriptome of normal primary human trabecular meshwork cells (HTM). We identified a significant number of differentially expressed genes and associated pathways that contribute to the pathogenesis of POAG. The differentially expressed genes were predominantly enriched in ECM regulation, TGF-β signalling, proliferation/apoptosis, inflammation/wound healing, MAPK signalling, oxidative stress and RHO signalling. Canonical pathway analysis confirmed the enrichment of RhoA signalling, inflammatory-related processes, ECM and cytoskeletal organisation in HTM cells in response to TGF-β2. We also identified novel genes and pathways that were affected after TGF-β2 treatment in the HTM, suggesting additional pathways are activated, including Nrf2, PI3K-Akt, MAPK and HIPPO signalling pathways. The identification and characterisation of TGF-β2 dependent differentially expressed genes and pathways in HTM cells is essential to understand the patho-physiology of glaucoma and to develop new therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-Wide Transcriptome Profiling of Human Trabecular Meshwork Cells Treated with TGF-β2.

Willoughby

Lester

Whysall

et al. 2021

Preprint

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“…Genomic DNAs were extracted from venous blood samples of each participant, which were anticoagulated with ethylenediaminetetraacetic acid (EDTA), by applying approach of phenol‐chloroform extraction and ethanol precipitation. Then, DNA was amplified with the aid of a PCR kit (Takara), and SNPs in MALAT1 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 and ANRIL 14 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 were genotyped using the single‐base end extension (SNaPshot) method, a genetic analyzer (model: ABI3130), and Genemapper software from ABI.…”

Section: Methodsmentioning

confidence: 99%

Significance of the lncRNAs MALAT1 and ANRIL in occurrence and development of glaucoma

Huang

Liang

Luo

et al. 2022

Clinical Laboratory Analysis

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Background: Primary open-angle glaucoma (POAG) is the commonest form of glaucoma which is estimated to cause bilaterally blind within 11.1 million people by 2020.Therefore, the primary objectives of this study were to investigate the clinical significance of single-nucleotide polymorphisms (SNPs) in the lncRNAs MALAT1 and ANRIL in a Chinese Han POAG cohort.Methods: Three hundred and forty-six glaucoma patients and 263 healthy controls were recruited, and totally 14 SNPs in MALAT1 and ANRIL were genotyped between the two populations. Results:The MALAT1 SNPs rs619586 (A>G), rs3200401 (C>T), and rs664589 (C>G) were associated with POAG risk, and the ANRIL SNPs rs2383207 (A>G), rs564398 (A>G), rs2157719 (A>G), rs7865618 (G>A), and rs4977574 (A>G) were associated with POAG (p < 0.05). The MALAT1 haplotypes ACG and ATC, comprised rs619586, rs3200401, and rs664589, increased POAG risk, and the ANRIL haplotype AAGAA, made up of rs2383207, rs7865618, rs4977574, rs564398, and rs2157719, show a significantly increased risk of POAG. In addition, rs619586 (A>G) of MALAT1 and rs564398/rs2157719 of ANRIL were associated with a smaller vertical cup-to-disc ratio, while rs619586 of MALAT1 and rs2383207/rs4977574 of ANRIL were associated with higher intraocular pressure in the POAG population. Conclusion: Single-nucleotide polymorphisms and haplotypes in ANRIL and MALAT1were associated with POAG onset in our study population, which provide more possibilities to POAG diagnosis and treatment.

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“…The nearest genes, approximately 100 kilobases (kb) away from the core CAD region, are two tumor suppressor genes (cyclin-dependent kinase inhibitors) CDKN2A and CDKN2B that play an important role in cell cycle regulation, apoptosis, senescence, aging, and in ammation which are processes strongly involved in atherogenesis. From a functional perspective CDKN2A and CDKN2B are potentially functional candidates genes to implicated in the pathogenesis of atherosclerosis [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Emerging role of circANRIL expression in peripheral blood mononuclear cells as a promising liquid biopsy diagnostic biomarker for coronary artery disease

Akan

Nyawawa²,

Nyangasa³

et al. 2022

Preprint

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Background: Long-non-coding RNAs (lncRNAs) are increasingly recognized to play major roles in coronary artery disease (CAD). ANRIL, a well-known lncRNA is located on the 9p21.3 locus which is the first reported CAD risk locus. This study aimed to evaluate the association of ANRIL and its transcript variants expressions with susceptibility to CAD as well as to investigate the impact of 9p21.3 locus single nucleotid polymorphisms (SNPs) on their expressions in adipose tissues and peripheral blood mononuclear cells (PBMCs) of Tanzanian study cohort.Methods: Expressions of ANRIL, and its variants; circANRIL (hsa_circ_0008574), NR003529, EU741058 and DQ485454 were detected by qRT-PCR in visceral adipose tissues (VAT) (epicardial adipose tissue (EAT) and mediastinal adipose tissue(MAT)), subcutaneous adipose tissue (SAT) and PBMCs of patients undergoing coronary artery bypass grafting due to CAD and non-CAD patients undergoing heart valve surgery. Five SNPs encompassing the 9p21.3 risk locus were genotyped in a cohort of 200 CAD patients an 220 non-CAD patients using qRT-PCR and their impact on gene expressions were further evaluated.Results: ANRIL expression was significantly up-regulated, while the expression of circANRIL significantly down-regulated in CAD patients compared to non-CAD patients. Also, increased circANRIL expression was determined to be significantly inversely associated with the severity of CAD. Moreover, rs10757278 and rs10811656 polymorphisms were significantly associated with expressions of ANRIL, EU741058, NR003529 and circANRIL in VAT and PBMCs. Decreased circANRIL levels were correlated with aggressive clinical characteristics. Moreover, the random forest model was evaluated to feature importance of CAD prediction. Accordingly, the receiver operating characteristics(ROC) curve analysis was evaluated and the result suggested that circANRIL has high diagnostic accuracy. The area under the ROC curve (AUC) was 0.9808, the optimal cut‐off value was 0.33, with a sensitivity of 1.0 and a specificity of 0.88.Conclusion: We report the first data demonstating the presence of, ANRIL and its transcript variants expressions in adipose tissues and PBMCs of CAD patients and the strong association between ANRIL expression and CAD. circANRIL having a synergetic effect with ANRIL plays a protective role in CAD pathogenesis. Therefore, altered circANRIL expression may become a potential diagnostic biomarker for early CAD diagnosis in Tanzania.

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Molecular Genetics and Functional Analysis Implicate CDKN2BAS1-CDKN2B Involvement in POAG Pathogenesis

Cited by 15 publications

References 54 publications

Genome-Wide Transcriptome Profiling of Human Trabecular Meshwork Cells Treated with TGF-β2.

Genome-Wide Transcriptome Profiling of Human Trabecular Meshwork Cells Treated with TGF-β2.

Significance of the lncRNAs MALAT1 and ANRIL in occurrence and development of glaucoma

Emerging role of circANRIL expression in peripheral blood mononuclear cells as a promising liquid biopsy diagnostic biomarker for coronary artery disease

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