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

Cells

Sushma Vishwakarma¹  Inderjeet Kaur¹  Tarjani Dave¹  Ian Danford²  Lana Verkuil²  Sonika Rathi²  Maxwell Pistilli²  JoanM. O’Brien²  VenkataR. M. Chavali²  HariniV. Gudiseva² 

[1] Prof Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad, Telangana 500034, India;Scheie Eye Institute, Department of Ophthalmology, Philadelphia, PA 19104, USA;

关键词: CDKN2B-AS1;    senescence;    Primary open-angle glaucoma (POAG);    trabecular meshwork cells;    African Americans;   

DOI  :  10.3390/cells9091934

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown