Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expression
Abstract Histone deacetylase-5 (HDAC5) is implicated in the pathogenesis of depression and the mechanistic pathways underlying the effects of antidepressant medications. We previously identified a novel HDAC5 inhibitor, T2943, with antidepressant properties that promote histone 3 lysine-14 acetylati...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-88670-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1825197336277549056 |
|---|---|
| author | Juan Du Ruyun Liu Lin Ma Yue Liu Wei Wei Ning Liu Qiuhua Cao Jianqiang Yu |
| author_facet | Juan Du Ruyun Liu Lin Ma Yue Liu Wei Wei Ning Liu Qiuhua Cao Jianqiang Yu |
| author_sort | Juan Du |
| collection | DOAJ |
| description | Abstract Histone deacetylase-5 (HDAC5) is implicated in the pathogenesis of depression and the mechanistic pathways underlying the effects of antidepressant medications. We previously identified a novel HDAC5 inhibitor, T2943, with antidepressant properties that promote histone 3 lysine-14 acetylation (H3K14ac) by inhibiting HDAC5 activity. In this study, we identify the core genes promoting transcription and expression following T2943-mediated upregulation of H3K14ac, highlighting Grid1 (GluD1) as a central gene. We used cleavage under targets and tagmentation (CUT&Tag), gene set enrichment analysis, and behavioral tests after GRID1 (glutamate receptor delta-1 subunit) knockdown. Gene ontology and pathway enrichment analysis via CUT&Tag suggested the following mechanism for the antidepressant action of T2943: T2943 inhibits HDAC5 activity to promote H3K14 acetylation. This modification loosens the chromatin structure, allowing transcription factors to bind to the Grid1 promoter region and enhance its transcription and expression. Upregulated GRID1 mediates signal transmission in neural pathways, restores the regenerative ability of hippocampal nerve cells, promotes nerve growth and synaptic formation, increases synapse numbers, and enhances synaptic function. Our findings highlight the therapeutic potential of targeting HDAC5 in depression and clarify the antidepressant mechanism of T2943. |
| format | Article |
| id | doaj-art-35d4c6f5225c4ed6b8f60272f87ab4a7 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-35d4c6f5225c4ed6b8f60272f87ab4a72025-02-09T12:28:09ZengNature PortfolioScientific Reports2045-23222025-02-0115111310.1038/s41598-025-88670-5Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expressionJuan Du0Ruyun Liu1Lin Ma2Yue Liu3Wei Wei4Ning Liu5Qiuhua Cao6Jianqiang Yu7Department of Pharmacology, School of Pharmacy, Ningxia Medical UniversityDepartment of Pharmacology, School of Pharmacy, Ningxia Medical UniversityDepartment of Pharmacology, School of Pharmacy, Ningxia Medical UniversityDepartment of Pharmacology, School of Pharmacy, Ningxia Medical UniversityDepartment of Pharmacology, School of Pharmacy, Ningxia Medical UniversityDepartment of Pharmacology, School of Pharmacy, Ningxia Medical UniversityVaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityDepartment of Pharmacology, School of Pharmacy, Ningxia Medical UniversityAbstract Histone deacetylase-5 (HDAC5) is implicated in the pathogenesis of depression and the mechanistic pathways underlying the effects of antidepressant medications. We previously identified a novel HDAC5 inhibitor, T2943, with antidepressant properties that promote histone 3 lysine-14 acetylation (H3K14ac) by inhibiting HDAC5 activity. In this study, we identify the core genes promoting transcription and expression following T2943-mediated upregulation of H3K14ac, highlighting Grid1 (GluD1) as a central gene. We used cleavage under targets and tagmentation (CUT&Tag), gene set enrichment analysis, and behavioral tests after GRID1 (glutamate receptor delta-1 subunit) knockdown. Gene ontology and pathway enrichment analysis via CUT&Tag suggested the following mechanism for the antidepressant action of T2943: T2943 inhibits HDAC5 activity to promote H3K14 acetylation. This modification loosens the chromatin structure, allowing transcription factors to bind to the Grid1 promoter region and enhance its transcription and expression. Upregulated GRID1 mediates signal transmission in neural pathways, restores the regenerative ability of hippocampal nerve cells, promotes nerve growth and synaptic formation, increases synapse numbers, and enhances synaptic function. Our findings highlight the therapeutic potential of targeting HDAC5 in depression and clarify the antidepressant mechanism of T2943.https://doi.org/10.1038/s41598-025-88670-5Histone deacetylase-5 inhibitorT2943DepressionHistone acetylationEpigenetics |
| spellingShingle | Juan Du Ruyun Liu Lin Ma Yue Liu Wei Wei Ning Liu Qiuhua Cao Jianqiang Yu Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expression Scientific Reports Histone deacetylase-5 inhibitor T2943 Depression Histone acetylation Epigenetics |
| title | Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expression |
| title_full | Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expression |
| title_fullStr | Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expression |
| title_full_unstemmed | Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expression |
| title_short | Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expression |
| title_sort | novel histone deacetylase 5 inhibitor t2943 exerts an anti depressive effect in mice by enhancing grid1 expression |
| topic | Histone deacetylase-5 inhibitor T2943 Depression Histone acetylation Epigenetics |
| url | https://doi.org/10.1038/s41598-025-88670-5 |
| work_keys_str_mv | AT juandu novelhistonedeacetylase5inhibitort2943exertsanantidepressiveeffectinmicebyenhancinggrid1expression AT ruyunliu novelhistonedeacetylase5inhibitort2943exertsanantidepressiveeffectinmicebyenhancinggrid1expression AT linma novelhistonedeacetylase5inhibitort2943exertsanantidepressiveeffectinmicebyenhancinggrid1expression AT yueliu novelhistonedeacetylase5inhibitort2943exertsanantidepressiveeffectinmicebyenhancinggrid1expression AT weiwei novelhistonedeacetylase5inhibitort2943exertsanantidepressiveeffectinmicebyenhancinggrid1expression AT ningliu novelhistonedeacetylase5inhibitort2943exertsanantidepressiveeffectinmicebyenhancinggrid1expression AT qiuhuacao novelhistonedeacetylase5inhibitort2943exertsanantidepressiveeffectinmicebyenhancinggrid1expression AT jianqiangyu novelhistonedeacetylase5inhibitort2943exertsanantidepressiveeffectinmicebyenhancinggrid1expression |