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

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          Abstract

          The genes in the 9p21 locus ( CDKN2B-AS1 & CDKN2B) are widely associated with Primary open-angle glaucoma (POAG). However, the functional importance of this locus in POAG pathogenesis is still unexplored. This study investigated the role of CDKN2BAS1-CDKN2B axis in POAG. We observed significant association of CDKN2B-AS1 SNP rs4977756 with POAG and its endophenotypic traits (vertical cup-disc ratio ( p = 0.033) and central corneal thickness ( p = 0.008)) by screening African American POAG cases ( n = 1567) and controls ( n = 1600). A luciferase reporter assay in Human embryonic kidney 293T (HEK293T) cells revealed that the region surrounding rs4977756 likely serves as a transcriptional repressor. siRNA-mediated knockdown of CDKN2B-AS1 in HEK293T cells and trabecular meshwork (TM) cells resulted in significantly increased expression of CDKN2B, which was also observed in human POAG ocular tissues. Pathway focused qRT-PCR gene expression analysis showed increased cellular senescence, TGFβ signaling and ECM deposition in TM cells after CDKN2B-AS1 suppression. In conclusion, we report that CDKN2B-AS1 may act as a regulator, and it could function by modulating the expression of CDKN2B. In addition, increase in CDKN2B levels due to CDKN2B-AS1 suppression may result in the senescence of trabecular meshwork cells leading to POAG pathogenesis.

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          Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a.

          Kyoko Yap, Side Li, Ana Muñoz-Cabello … (2010)
          Expression of the INK4b/ARF/INK4a tumor suppressor locus in normal and cancerous cell growth is controlled by methylation of histone H3 at lysine 27 (H3K27me) as directed by the Polycomb group proteins. The antisense noncoding RNA ANRIL of the INK4b/ARF/INK4a locus is also important for expression of the protein-coding genes in cis, but its mechanism has remained elusive. Here we report that chromobox 7 (CBX7) within the polycomb repressive complex 1 binds to ANRIL, and both CBX7 and ANRIL are found at elevated levels in prostate cancer tissues. In concert with H3K27me recognition, binding to RNA contributes to CBX7 function, and disruption of either interaction impacts the ability of CBX7 to repress the INK4b/ARF/INK4a locus and control senescence. Structure-guided analysis reveals the molecular interplay between noncoding RNA and H3K27me as mediated by the conserved chromodomain. Our study suggests a mechanism by which noncoding RNA participates directly in epigenetic transcriptional repression. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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            Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.

            Y Kotake, T Nakagawa, K Kitagawa … (2011)
            A 42 kb region on human chromosome 9p21 encodes for three distinct tumor suppressors, p16(INK4A), p14(ARF) and p15(INK4B), and is altered in an estimated 30-40% of human tumors. The expression of the INK4A-ARF-INK4B gene cluster is silenced by polycomb during normal cell growth and is activated by oncogenic insults and during aging. How the polycomb is recruited to repress this gene cluster is unclear. Here, we show that expression of oncogenic Ras, which stimulates the expression of p15(INK4B) and p16(INK4A), but not p14(ARF), inhibits the expression of ANRIL (antisense non-coding RNA in the INK4 locus), a 3.8 kb-long non-coding RNA expressed in the opposite direction from INK4A-ARF-INK4B. We show that the p15(INK4B) locus is bound by SUZ12, a component of polycomb repression complex 2 (PRC2), and is H3K27-trimethylated. Notably, depletion of ANRIL disrupts the SUZ12 binding to the p15(INK4B) locus, increases the expression of p15(INK4B), but not p16(INK4A) or p14(ARF), and inhibits cellular proliferation. Finally, RNA immunoprecipitation demonstrates that ANRIL binds to SUZ12 in vivo. Collectively, these results suggest a model in which ANRIL binds to and recruits PRC2 to repress the expression of p15(INK4B) locus.
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              TGF-β Family Signaling in the Control of Cell Proliferation and Survival

              Xiao-Fan Wang, Peter B. Alexander, Yun Zhang (2017)
              The transforming growth factor β (TGF-β) family controls many fundamental aspects of cellular behavior. With advances in the molecular details of the TGF-β signaling cascade and its cross talk with other signaling pathways, we now have a more coherent understanding of the cytostatic program induced by TGF-β. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated by TGF-β and determine a cell's proliferation and survival, apoptosis, dormancy, autophagy, and senescence. The difficulty in defining TGF-β's roles partly stems from the context-dependent nature of TGF-β signaling. Here, we review our current understanding and recent progress on the biological effects of TGF-β at the cellular level, with the hope of providing a framework for understanding how cells respond to TGF-β signals in specific contexts, and why disruption of such mechanisms may result in different human diseases including cancer.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 21 August 2020
                Publication date Collection: September 2020
                Volume: 9
                Issue: 9
                Electronic Location Identifier: 1934
                Affiliations
                [1 ]Scheie Eye Institute, Department of Ophthalmology, Philadelphia, PA 19104, USA; Sonika.Rathi@ 123456pennmedicine.upenn.edu (S.R.); ian.danford@ 123456gmail.com (I.D.); gudiseva@ 123456pennmedicine.upenn.edu (H.V.G.); lanav@ 123456pennmedicine.upenn.edu (L.V.); pistilli@ 123456pennmedicine.upenn.edu (M.P.)
                [2 ]Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA
                [3 ]Prof Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad, Telangana 500034, India; svishwakarma17@ 123456gmail.com (S.V.); inderjeet@ 123456lvpei.org (I.K.)
                [4 ]Ophthalmic Plastic Surgery Service, Prof Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad, Telangana 500034, India; tarjani@ 123456lvpei.org
                Author notes
                [* ]Correspondence: Joan.O’ Brien@ 123456pennmedicine.upenn.edu (J.M.O.); vchavali@ 123456pennmedicine.upenn.edu (V.R.M.C.)
                [†]

                Authors contributed equally.

                Author information
                https://orcid.org/0000-0002-4266-4150
                https://orcid.org/0000-0003-3660-5039
                https://orcid.org/0000-0003-3439-3490
                Article
                Publisher ID: cells-09-01934
                DOI: 10.3390/cells9091934
                PMC ID: 7564117
                PubMed ID: 32825664
                SO-VID: 64cf6187-d289-45b4-aa71-0eae885acb2e
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 16 June 2020
                Date accepted : 17 August 2020
                Categories
                Subject: Article

                Keywords: cdkn2b-as1,senescence,primary open-angle glaucoma (poag),trabecular meshwork cells,african americans
                Data availability:
                Keywords: cdkn2b-as1, senescence, primary open-angle glaucoma (poag), trabecular meshwork cells, african americans

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