{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:11:44Z","timestamp":1781284304489,"version":"3.54.1"},"reference-count":45,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"RPB Stein Innovation","award":["STTR NIH R41 EY035180-01"],"award-info":[{"award-number":["STTR NIH R41 EY035180-01"]}]},{"name":"Pennsylvania State University College of Medicine via the Office of the Vice Dean of Research and Graduate Students","award":["STTR NIH R41 EY035180-01"],"award-info":[{"award-number":["STTR NIH R41 EY035180-01"]}]},{"name":"Pennsylvania Department of Health using Tobacco Settlement Funds (CURE)","award":["STTR NIH R41 EY035180-01"],"award-info":[{"award-number":["STTR NIH R41 EY035180-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We have previously demonstrated the ability of inhibitors of LSD1 and HDAC1 to block rod degeneration, preserve vision, maintain transcription of rod photoreceptor genes, and downregulate transcripts involved in cell death, gliosis, and inflammation in the mouse model of Retinitis Pigmentosa (RP), rd10. To extend our findings, we tested the hypothesis that this effect was due to altered chromatin structure by using a range of inhibitors of chromatin condensation to prevent photoreceptor degeneration in the rd10 mouse model. We used inhibitors for both G9A\/GLP, which catalyzes methylation of H3K9, and EZH2, which catalyzes trimethylation of H3K27, and compared them to the actions of inhibitors of LSD1 and HDAC. All the inhibitors are likely to decondense chromatin and all preserve, to different extents, retinas from degeneration in rd10 mice, but they act through different metabolic pathways. One group of inhibitors, modifiers for LSD1 and EZH2, demonstrate a high level of maintenance of rod-specific transcripts, activation of Ca2+ and Wnt signaling pathways with the inhibition of antigen processing and presentation, immune response, and microglia phagocytosis. Another group of inhibitors, modifiers for HDAC and G9A\/GLP, work through upregulation of NGF-stimulated transcription, while downregulating genes belong to immune response, extracellular matrix, cholesterol signaling, and programmed cell death. Our results provide robust support for our hypothesis that inhibition of chromatin condensation can be sufficient to prevent rod death in rd10 mice.<\/jats:p>","DOI":"10.3390\/cells14130961","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T10:44:41Z","timestamp":1750761881000},"page":"961","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Epigenetic Modifiers to Treat Retinal Degenerative Diseases"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6164-262X","authenticated-orcid":false,"given":"Evgenya Y.","family":"Popova","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Penn State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1365-1000","authenticated-orcid":false,"given":"Lisa","family":"Schneper","sequence":"additional","affiliation":[{"name":"Department of Molecular and Precision Medicine, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4936-5564","authenticated-orcid":false,"given":"Aswathy","family":"Sebastian","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Huck Institute of Life Sciences, Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8366-984X","authenticated-orcid":false,"given":"Istvan","family":"Albert","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Huck Institute of Life Sciences, Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"Tombran-Tink","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Penn State University College of Medicine, Hershey, PA 17033, USA"},{"name":"Skyran Biologics, Harrisburg, PA 17112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin J.","family":"Barnstable","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Penn State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.cell.2009.01.052","article-title":"Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution","volume":"137","author":"Solovei","year":"2009","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17895","DOI":"10.1074\/jbc.M113.452144","article-title":"Developmentally regulated linker histone H1c promotes heterochromatin condensation and mediates structural integrity of rod photoreceptors in mouse retina","volume":"288","author":"Popova","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hughes, A.E., Enright, J.M., Myers, C.A., Shen, S.Q., and Corbo, J.C. (2017). Cell Type-Specific Epigenomic Analysis Reveals a Uniquely Closed Chromatin Architecture in Mouse Rod Photoreceptors. Sci. Rep., 7.","DOI":"10.1038\/srep43184"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Popova, E.Y., Xu, X., DeWan, A.T., Salzberg, A.C., Berg, A., Hoh, J., Zhang, S.S., Barnstable, C.J., and Englert, C. (2012). Stage and gene specific signatures defined by histones H3K4me2 and H3K27me3 accompany mammalian retina maturation in vivo. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046867"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/nn0109-5","article-title":"Retinitis pigmentosa: Cone photoreceptors starving to death","volume":"12","author":"Bovolenta","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3904","DOI":"10.1073\/pnas.1922925117","article-title":"Understanding the genetic architecture of human retinal degenerations","volume":"117","author":"Hejtmancik","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1073\/pnas.1913179117","article-title":"Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases","volume":"117","author":"Hanany","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.preteyeres.2017.10.004","article-title":"Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives","volume":"63","author":"Dias","year":"2018","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.preteyeres.2015.06.005","article-title":"Pharmacological approaches to retinitis pigmentosa: A laboratory perspective","volume":"48","author":"Guadagni","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1167\/tvst.7.4.6","article-title":"Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps","volume":"7","author":"Duncan","year":"2018","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6775","DOI":"10.1523\/JNEUROSCI.3102-20.2021","article-title":"Inhibition of epigenetic modifiers LSD1 and HDAC1 blocks rod photoreceptor death in mouse models of Retinitis Pigmentosa","volume":"41","author":"Popova","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.molcel.2018.01.002","article-title":"PKC\u03b1-LSD1-NF-\u03baB-Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response","volume":"69","author":"Kim","year":"2018","journal-title":"Mol. Cell."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.1074\/jbc.M209572200","article-title":"Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65","volume":"278","author":"Kiernan","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1111\/j.1349-7006.2011.01904.x","article-title":"Histone deacetylase inhibitors block nuclear factor-\u03baB-dependent transcription by interfering with RNA polymerase II recruitment","volume":"102","author":"Furumai","year":"2011","journal-title":"Cancer Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/s41419-018-0349-8","article-title":"DZNep inhibits H3K27me3 deposition and delays retinal degeneration in the rd1 mice","volume":"9","author":"Zheng","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"172452","DOI":"10.1016\/j.ejphar.2019.172452","article-title":"EZH2 inhibitor DZNep modulates microglial activation and protects against ischaemic brain injury after experimental stroke","volume":"857","author":"Chen","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mbefo, M., Berger, A., Schouwey, K., G\u00e9rard, X., Kostic, C., Beryozkin, A., Sharon, D., Dolfuss, H., Munier, F., and Tran, H.V. (2021). Enhancer of Zeste Homolog 2 (EZH2) Contributes to Rod Photoreceptor Death Process in Several Forms of Retinal Degeneration and Its Activity Can Serve as a Biomarker for Therapy Efficacy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179331"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11591","DOI":"10.18632\/aging.102558","article-title":"Pharmacological inhibition of G9a\/GLP restores cognition and reduces oxidative stress, neuroinflammation and \u03b2-Amyloid plaques in an early-onset Alzheimer\u2019s disease mouse model","volume":"11","author":"Kondengaden","year":"2019","journal-title":"Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nm.4257","article-title":"Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome","volume":"23","author":"Kim","year":"2017","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/286231a0","article-title":"Monoclonal antibodies which recognize different cell types in the rat retina","volume":"286","author":"Barnstable","year":"1980","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.1073\/pnas.0508214103","article-title":"Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors","volume":"103","author":"Akimoto","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.mex.2015.01.002","article-title":"Quick and reliable method for retina dissociation and separation of rod photoreceptor perikarya from adult mice","volume":"2","author":"Feodorova","year":"2015","journal-title":"MethodsX"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1384805","DOI":"10.3389\/fnins.2024.1384805","article-title":"Temporal changes in mouse hippocampus transcriptome after pilocarpine-induced seizures","volume":"18","author":"Popova","year":"2024","journal-title":"Front Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq--a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4563","DOI":"10.1007\/s12035-015-9395-8","article-title":"LSD1-Mediated Demethylation of H3K4me2 Is Required for the Transition from Late Progenitor to Differentiated Mouse Rod Photoreceptor","volume":"53","author":"Popova","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1074\/jbc.M116.756643","article-title":"Histone Deacetylase 1 Is Essential for Rod Photoreceptor Differentiation by Regulating Acetylation at Histone H3 Lysine 9 and Histone H4 Lysine 12 in the Mouse Retina","volume":"292","author":"Ferreira","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1016\/j.ymthe.2024.05.034","article-title":"Newly developed oral bioavailable EHMT2 inhibitor as a potential epigenetic therapy for Prader-Willi syndrome","volume":"32","author":"Wang","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.neuron.2017.04.022","article-title":"The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis","volume":"94","author":"Aldiri","year":"2017","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Karademir, D., Todorova, V., Ebner, L.J.A., Samardzija, M., and Grimm, C. (2022). Single-cell RNA sequencing of the retina in a model of retinitis pigmentosa reveals early responses to degeneration in rods and cones. BMC Biol., 20.","DOI":"10.1186\/s12915-022-01280-9"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"216143","DOI":"10.1016\/j.canlet.2023.216143","article-title":"EZH2 and NF-\u03baB: A context-dependent crosstalk and transcriptional regulation in cancer","volume":"560","author":"Kaur","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Weng, H.R., Taing, K., Chen, L., and Penney, A. (2023). EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain. Cells, 12.","DOI":"10.3390\/cells12071058"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1093\/hmg\/ddaa158","article-title":"Epigenetic hallmarks of age-related macular degeneration are recapitulated in a photosensitive mouse model","volume":"29","author":"Luu","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_36","first-page":"4462","article-title":"HDAC inhibition in the cpfl1 mouse protects degenerating cone photoreceptors in vivo","volume":"25","author":"Comitato","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/978-3-319-75402-4_45","article-title":"Primary Rod and Cone Degeneration Is Prevented by HDAC Inhibition","volume":"1074","author":"Petridou","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e15659","DOI":"10.7717\/peerj.15659","article-title":"HDAC inhibition delays photoreceptor loss in","volume":"11","author":"Dong","year":"2023","journal-title":"PeerJ"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1186\/s12974-020-02028-4","article-title":"Neuroprotective epi-drugs quench the inflammatory response and microglial\/macrophage activation in a mouse model of permanent brain ischemia","volume":"17","author":"Mota","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Schioppa, T., Nguyen, H.O., Tiberio, L., Sozio, F., Gaudenzi, C., Passari, M., Del Prete, A., Bosisio, D., and Salvi, V. (2022). Inhibition of Class I Histone Deacetylase Activity Blocks the Induction of TNFAIP3 Both Directly and Indirectly via the Suppression of Endogenous TNF-\u03b1. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179752"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1093\/hmg\/ddz299","article-title":"Rhodopsin signaling mediates light-induced photoreceptor cell death in rd10 mice through a transducin-independent mechanism","volume":"29","author":"Sundar","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Weh, E., Scott, K., Wubben, T.J., and Besirli, C.G. (2022). Dark-reared rd10 mice experience rapid photoreceptor degeneration with short exposure to room-light during in vivo retinal imaging. Exp. Eye Res., 215.","DOI":"10.1016\/j.exer.2021.108913"},{"key":"ref_43","first-page":"1571","article-title":"Loss of Bmi1 causes anomalies in retinal development and degeneration of cone photoreceptors","volume":"143","author":"Barabino","year":"2016","journal-title":"Development"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Popova, E.Y., and Barnstable, C.J. (2019). Insights Into the Epigenetics of Retinal Development and Diseases In Epigenetics and Regeneration, Academic Press.","DOI":"10.1016\/B978-0-12-814879-2.00016-9"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kerenyi, M.A., Shao, Z., Hsu, Y.J., Guo, G., Luc, S., O\u2019Brien, K., Fujiwara, Y., Peng, C., Nguyen, M., and Orkin, S.H. (2013). Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. Elife, 2.","DOI":"10.7554\/eLife.00633"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/13\/961\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:57:18Z","timestamp":1760032638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/13\/961"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":45,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["cells14130961"],"URL":"https:\/\/doi.org\/10.3390\/cells14130961","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.05.22.655558","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,23]]}}}