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Functional study of the AMD-associated gene TMEM97 in retinal pigmented epithelium using CRISPR interference
Abstract
Age-related macular degeneration (AMD) is a blinding disease characterised by dysfunction of the retinal pigmented epithelium (RPE) which culminates in disruption or loss of the neurosensory retina. Genome-wide association studies have identified >65 genetic risk factors for AMD, including the TMEM97 locus. TMEM97 encodes the Sigma-2 receptor which is involved in apoptosis and cytotoxicity across a range of neurodegenerative diseases. However, the expression pattern of TMEM97 in the human retina and its functional role in retinal cells has remained elusive. Here we utilised CRISPR interference (CRISPRi) to investigate the functional role of TMEM97 in the retina. Transcriptome analysis of all major cell types within the human retina showed that TMEM97 is expressed in the RPE, retinal ganglion cells (RGCs) and amacrine cells. Using CRISPRi, we performed loss-of-function study of TMEM97 in the human RPE cell line, ARPE19. We generated a stable ARPE19 cell line expressing dCas9-KRAB which facilitated knockdown of TMEM97 using specific sgRNAs. Our results show that knockdown of TMEM97 in ARPE19 exerts a protective effect against oxidative stress-induced cell death. This work provides the first functional study of TMEM97 in RPE and supports the role of TMEM97 in AMD pathobiology. Our study highlights the potential for using CRISPRi to study AMD genetics, and the CRISPRi cell line generated here provided an useful in vitro tool for functional studies of other AMD-associated genes.
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In the retina, S2R is expressed in retinal pigment epithelium cells, photoreceptors, and retinal ganglion cells.
“In the retina, S2R is expressed in several cell types including the retinal pigment epithelium cells, photoreceptors, and retinal ganglion cells [70,71,72,73,74].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [70]
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Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation
Dominguez, A. A., Lim, W. A., & Qi, L. S. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2015.2 · Cited by 832 · cited 1×
“Moreover, recent development has highlighted the use of a nuclease-null Cas9 coupled with transcriptional repressors to modulate endogenous gene expression levels, termed CRISPR interference (CRISPRi), which offers a robust system to study gene function [13].”
BackgroundYu, Y., Bhangale, T. R., Fagerness, J., Ripke, S., Thorleifsson, G., Tan, P. L., Souied, E. H., Richardson, A. J., Merriam, J. E., Buitendijk, G. H. S., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr270 · Cited by 254 · cited 1×
“[5] Yu Y, Bhangale TR, Fagerness J, Ripke S, Thorleifsson G, Tan PL, et al.”
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Lizama, B. N., Kahle, J., Catalano, S. M., Caggiano, A. O., Grundman, M., & Hamby, M. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076251 · Cited by 54
Metadata
- Authors
- Wang, J.-H., Urrutia-Cabrera, D., Mora, S. M., Nguyen, T., Hung, S., Hewitt, A. W., Edwards, T. L., & Wong, R. C. B.
- ORCID
- Wong, Raymond C.B.
- Publisher
- openRxiv
- Published
- 2020-07-11
- Cited by
- 4
- References
- 2
- Type
- Preprint
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