HDAC inhibition delays photoreceptor loss in Pde6b mutant mice of retinitis pigmentosa: insights from scRNA-seq and CUT&Tag
Purpose This research aimed to ascertain the neuroprotective effect of histone deacetylase (HDAC) inhibition on retinal photoreceptors in Pde6brd1 mice, a model of retinitis pigmentosa (RP). Methods Single-cell RNA-sequencing (scRNA-seq) explored HDAC and poly (ADP-ribose) polymerase (PARP)-related...
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PeerJ Inc.
2023-07-01
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| Online Access: | https://peerj.com/articles/15659.pdf |
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| author | Yujie Dong Jie Yan Wenrong Xu François Paquet-Durand Zhulin Hu Kangwei Jiao |
| author_facet | Yujie Dong Jie Yan Wenrong Xu François Paquet-Durand Zhulin Hu Kangwei Jiao |
| author_sort | Yujie Dong |
| collection | DOAJ |
| description | Purpose This research aimed to ascertain the neuroprotective effect of histone deacetylase (HDAC) inhibition on retinal photoreceptors in Pde6brd1 mice, a model of retinitis pigmentosa (RP). Methods Single-cell RNA-sequencing (scRNA-seq) explored HDAC and poly (ADP-ribose) polymerase (PARP)-related gene expression in both Pde6b-mutant rd1 and wild-type (WT) mice. The CUT&Tag method was employed to examine the functions of HDAC in rd1 mice. Organotypic retinal explant cultures from WT and rd1 mice were exposed to the HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) postnatally, from day 5 to day 11. The terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to quantify the percentage of photoreceptor loss in the outer nuclear layer (ONL). HDAC activity was confirmed to be inhibited by SAHA through an HDAC activity assay. Moreover, the study evaluated PARP activity, a key driver of the initial response to DNA damage during photoreceptor degeneration, following HDAC inhibition. Results The scRNA-seq revealed that diverse roles of HDAC and PARP isoforms in photoreceptor cell death. HDAC-related genes appeared to regulate cell death and primary immunodeficiency. Alterations in HDAC activity were consistent with the TUNEL-positive cells in the ONL at different time points. Notably, SAHA significantly postponed photoreceptor loss and decreased HDAC and PARP activity, thereby implicating both in the same degenerative pathway. Conclusions This study highlights that the interaction between HDAC inhibition and PARP can delay photoreceptor cell death, proposing a promising therapeutic approach for RP. |
| first_indexed | 2024-03-09T06:54:38Z |
| format | Article |
| id | doaj.art-e344d66aae154fbea36ea7e15481618a |
| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T06:54:38Z |
| publishDate | 2023-07-01 |
| publisher | PeerJ Inc. |
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| spelling | doaj.art-e344d66aae154fbea36ea7e15481618a2023-12-03T10:08:46ZengPeerJ Inc.PeerJ2167-83592023-07-0111e1565910.7717/peerj.15659HDAC inhibition delays photoreceptor loss in Pde6b mutant mice of retinitis pigmentosa: insights from scRNA-seq and CUT&TagYujie Dong0Jie Yan1Wenrong Xu2François Paquet-Durand3Zhulin Hu4Kangwei Jiao5Kunming Medical University, Kunming, Yunnan, ChinaKey Laboratory of Yunnan Province, Yunnan Eye Institute, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, Yunnan, ChinaKey Laboratory of Yunnan Province, Yunnan Eye Institute, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, Yunnan, ChinaInstitute for Ophthalmic Research, Eberhard-Karls-Universität Tübingen, Tübingen, GermanyKey Laboratory of Yunnan Province, Yunnan Eye Institute, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, Yunnan, ChinaKey Laboratory of Yunnan Province, Yunnan Eye Institute, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, Yunnan, ChinaPurpose This research aimed to ascertain the neuroprotective effect of histone deacetylase (HDAC) inhibition on retinal photoreceptors in Pde6brd1 mice, a model of retinitis pigmentosa (RP). Methods Single-cell RNA-sequencing (scRNA-seq) explored HDAC and poly (ADP-ribose) polymerase (PARP)-related gene expression in both Pde6b-mutant rd1 and wild-type (WT) mice. The CUT&Tag method was employed to examine the functions of HDAC in rd1 mice. Organotypic retinal explant cultures from WT and rd1 mice were exposed to the HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) postnatally, from day 5 to day 11. The terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to quantify the percentage of photoreceptor loss in the outer nuclear layer (ONL). HDAC activity was confirmed to be inhibited by SAHA through an HDAC activity assay. Moreover, the study evaluated PARP activity, a key driver of the initial response to DNA damage during photoreceptor degeneration, following HDAC inhibition. Results The scRNA-seq revealed that diverse roles of HDAC and PARP isoforms in photoreceptor cell death. HDAC-related genes appeared to regulate cell death and primary immunodeficiency. Alterations in HDAC activity were consistent with the TUNEL-positive cells in the ONL at different time points. Notably, SAHA significantly postponed photoreceptor loss and decreased HDAC and PARP activity, thereby implicating both in the same degenerative pathway. Conclusions This study highlights that the interaction between HDAC inhibition and PARP can delay photoreceptor cell death, proposing a promising therapeutic approach for RP.https://peerj.com/articles/15659.pdfRetinitis pigmentosaHereditary retinal neurodegenerative disordersPhotoreceptor cellsHistone deacetylasesPoly (ADP-ribose) polymerasesCell death mechanisms |
| spellingShingle | Yujie Dong Jie Yan Wenrong Xu François Paquet-Durand Zhulin Hu Kangwei Jiao HDAC inhibition delays photoreceptor loss in Pde6b mutant mice of retinitis pigmentosa: insights from scRNA-seq and CUT&Tag PeerJ Retinitis pigmentosa Hereditary retinal neurodegenerative disorders Photoreceptor cells Histone deacetylases Poly (ADP-ribose) polymerases Cell death mechanisms |
| title | HDAC inhibition delays photoreceptor loss in Pde6b mutant mice of retinitis pigmentosa: insights from scRNA-seq and CUT&Tag |
| title_full | HDAC inhibition delays photoreceptor loss in Pde6b mutant mice of retinitis pigmentosa: insights from scRNA-seq and CUT&Tag |
| title_fullStr | HDAC inhibition delays photoreceptor loss in Pde6b mutant mice of retinitis pigmentosa: insights from scRNA-seq and CUT&Tag |
| title_full_unstemmed | HDAC inhibition delays photoreceptor loss in Pde6b mutant mice of retinitis pigmentosa: insights from scRNA-seq and CUT&Tag |
| title_short | HDAC inhibition delays photoreceptor loss in Pde6b mutant mice of retinitis pigmentosa: insights from scRNA-seq and CUT&Tag |
| title_sort | hdac inhibition delays photoreceptor loss in pde6b mutant mice of retinitis pigmentosa insights from scrna seq and cut tag |
| topic | Retinitis pigmentosa Hereditary retinal neurodegenerative disorders Photoreceptor cells Histone deacetylases Poly (ADP-ribose) polymerases Cell death mechanisms |
| url | https://peerj.com/articles/15659.pdf |
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