Functional microRNA targetome undergoes degeneration-induced shift in the retina
Abstract Background MicroRNA (miRNA) play a significant role in the pathogenesis of complex neurodegenerative diseases including age-related macular degeneration (AMD), acting as post-transcriptional gene suppressors through their association with argonaute 2 (AGO2) - a key member of the RNA Induced...
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| Format: | Article |
| Language: | English |
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BMC
2021-08-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-021-00478-9 |
| _version_ | 1824043036853665792 |
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| author | Joshua A. Chu-Tan Adrian V. Cioanca Zhi-Ping Feng Yvette Wooff Ulrike Schumann Riemke Aggio-Bruce Hardip Patel Matt Rutar Katherine Hannan Konstantin Panov Jan Provis Riccardo Natoli |
| author_facet | Joshua A. Chu-Tan Adrian V. Cioanca Zhi-Ping Feng Yvette Wooff Ulrike Schumann Riemke Aggio-Bruce Hardip Patel Matt Rutar Katherine Hannan Konstantin Panov Jan Provis Riccardo Natoli |
| author_sort | Joshua A. Chu-Tan |
| collection | DOAJ |
| description | Abstract Background MicroRNA (miRNA) play a significant role in the pathogenesis of complex neurodegenerative diseases including age-related macular degeneration (AMD), acting as post-transcriptional gene suppressors through their association with argonaute 2 (AGO2) - a key member of the RNA Induced Silencing Complex (RISC). Identifying the retinal miRNA/mRNA interactions in health and disease will provide important insight into the key pathways miRNA regulate in disease pathogenesis and may lead to potential therapeutic targets to mediate retinal degeneration. Methods To identify the active miRnome targetome interactions in the healthy and degenerating retina, AGO2 HITS-CLIP was performed using a rodent model of photoreceptor degeneration. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data was performed to identify the cellular location of AGO2 and key members of the microRNA targetome in the retina. AGO2 findings were verified by in situ hybridization (RNA) and immunohistochemistry (protein). Results Analysis revealed a similar miRnome between healthy and damaged retinas, however, a shift in the active targetome was observed with an enrichment of miRNA involvement in inflammatory pathways. This shift was further demonstrated by a change in the seed binding regions of miR-124-3p, the most abundant retinal AGO2-bound miRNA, and has known roles in regulating retinal inflammation. Additionally, photoreceptor cluster miR-183/96/182 were all among the most highly abundant miRNA bound to AGO2. Following damage, AGO2 expression was localized to the inner retinal layers and more in the OLM than in healthy retinas, indicating a locational miRNA response to retinal damage. Conclusions This study provides important insight into the alteration of miRNA regulatory activity that occurs as a response to retinal degeneration and explores the miRNA-mRNA targetome as a consequence of retinal degenerations. Further characterisation of these miRNA/mRNA interactions in the context of the degenerating retina may provide an important insight into the active role these miRNA may play in diseases such as AMD. |
| first_indexed | 2024-12-22T23:50:33Z |
| format | Article |
| id | doaj.art-e8092aeac0204c3e936b785d776b9dc5 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-22T23:50:33Z |
| publishDate | 2021-08-01 |
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| series | Molecular Neurodegeneration |
| spelling | doaj.art-e8092aeac0204c3e936b785d776b9dc52022-12-21T18:08:08ZengBMCMolecular Neurodegeneration1750-13262021-08-0116112110.1186/s13024-021-00478-9Functional microRNA targetome undergoes degeneration-induced shift in the retinaJoshua A. Chu-Tan0Adrian V. Cioanca1Zhi-Ping Feng2Yvette Wooff3Ulrike Schumann4Riemke Aggio-Bruce5Hardip Patel6Matt Rutar7Katherine Hannan8Konstantin Panov9Jan Provis10Riccardo Natoli11Eccles Institute of Neuroscience, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonEccles Institute of Neuroscience, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonThe ANU Bioinformatics Consultancy, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonEccles Institute of Neuroscience, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonEccles Institute of Neuroscience, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonEccles Institute of Neuroscience, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonThe ANU Bioinformatics Consultancy, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonSchool of Biomedical Sciences, The University of MelbourneACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonSchool of Biological Sciences Queen’s University BelfastEccles Institute of Neuroscience, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonEccles Institute of Neuroscience, The John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, ActonAbstract Background MicroRNA (miRNA) play a significant role in the pathogenesis of complex neurodegenerative diseases including age-related macular degeneration (AMD), acting as post-transcriptional gene suppressors through their association with argonaute 2 (AGO2) - a key member of the RNA Induced Silencing Complex (RISC). Identifying the retinal miRNA/mRNA interactions in health and disease will provide important insight into the key pathways miRNA regulate in disease pathogenesis and may lead to potential therapeutic targets to mediate retinal degeneration. Methods To identify the active miRnome targetome interactions in the healthy and degenerating retina, AGO2 HITS-CLIP was performed using a rodent model of photoreceptor degeneration. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data was performed to identify the cellular location of AGO2 and key members of the microRNA targetome in the retina. AGO2 findings were verified by in situ hybridization (RNA) and immunohistochemistry (protein). Results Analysis revealed a similar miRnome between healthy and damaged retinas, however, a shift in the active targetome was observed with an enrichment of miRNA involvement in inflammatory pathways. This shift was further demonstrated by a change in the seed binding regions of miR-124-3p, the most abundant retinal AGO2-bound miRNA, and has known roles in regulating retinal inflammation. Additionally, photoreceptor cluster miR-183/96/182 were all among the most highly abundant miRNA bound to AGO2. Following damage, AGO2 expression was localized to the inner retinal layers and more in the OLM than in healthy retinas, indicating a locational miRNA response to retinal damage. Conclusions This study provides important insight into the alteration of miRNA regulatory activity that occurs as a response to retinal degeneration and explores the miRNA-mRNA targetome as a consequence of retinal degenerations. Further characterisation of these miRNA/mRNA interactions in the context of the degenerating retina may provide an important insight into the active role these miRNA may play in diseases such as AMD.https://doi.org/10.1186/s13024-021-00478-9RetinamicroRNAmRNARetinal degenerationArgonauteHITS-CLIP |
| spellingShingle | Joshua A. Chu-Tan Adrian V. Cioanca Zhi-Ping Feng Yvette Wooff Ulrike Schumann Riemke Aggio-Bruce Hardip Patel Matt Rutar Katherine Hannan Konstantin Panov Jan Provis Riccardo Natoli Functional microRNA targetome undergoes degeneration-induced shift in the retina Molecular Neurodegeneration Retina microRNA mRNA Retinal degeneration Argonaute HITS-CLIP |
| title | Functional microRNA targetome undergoes degeneration-induced shift in the retina |
| title_full | Functional microRNA targetome undergoes degeneration-induced shift in the retina |
| title_fullStr | Functional microRNA targetome undergoes degeneration-induced shift in the retina |
| title_full_unstemmed | Functional microRNA targetome undergoes degeneration-induced shift in the retina |
| title_short | Functional microRNA targetome undergoes degeneration-induced shift in the retina |
| title_sort | functional microrna targetome undergoes degeneration induced shift in the retina |
| topic | Retina microRNA mRNA Retinal degeneration Argonaute HITS-CLIP |
| url | https://doi.org/10.1186/s13024-021-00478-9 |
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