JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain
Abstract Midbrain dopamine (mDA) neurons participate in a wide range of brain functions through an intricate regulation of DA biosynthesis. The epigenetic factors and mechanisms in this process are not well understood. Here we report that histone demethylase JMJD3 is a critical regulator for DA bios...
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| Format: | Article |
| Language: | English |
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BMC
2024-12-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01912-x |
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| author | Xi-Biao He Fang Guo Wei Zhang Jiacheng Fan Weidong Le Qi Chen Yongjun Ma Yong Zheng Sang-Hun Lee Hui-Jing Wang Yi Wu Qinming Zhou Rui Yang |
| author_facet | Xi-Biao He Fang Guo Wei Zhang Jiacheng Fan Weidong Le Qi Chen Yongjun Ma Yong Zheng Sang-Hun Lee Hui-Jing Wang Yi Wu Qinming Zhou Rui Yang |
| author_sort | Xi-Biao He |
| collection | DOAJ |
| description | Abstract Midbrain dopamine (mDA) neurons participate in a wide range of brain functions through an intricate regulation of DA biosynthesis. The epigenetic factors and mechanisms in this process are not well understood. Here we report that histone demethylase JMJD3 is a critical regulator for DA biosynthesis in adult mouse mDA neurons. Mice carrying Jmjd3 conditional knockout or undergoing pharmaceutical inhibition of JMJD3 showed consistent reduction of DA content in midbrain and striatum. Histological examination of both mice confirmed that TH and NURR1, two key molecules in DA biosynthesis pathway, were decreased in mDA neurons. Mechanistic experiments in vivo and in vitro further demonstrated that the transcriptions of Th and Nurr1 in mDA neurons were suppressed by JMJD3 deficiency, because of increased repressive H3K27me3 and attenuated bindings of JMJD3 and NURR1 on the promoters of both genes. On behavioral level, a significant prolonged inflammation-induced mechanical hyperalgesia was found in conditional knockout mice regardless of sex and age, whereas motor function appeared to be intact. Our findings establish a novel link between DA level in mDA neurons with intrinsic JMJD3 activity, and suggest prolonged chronic inflammatory pain as a major loss-of-function consequence. |
| format | Article |
| id | doaj-art-1a4be39c57f54c89a10a613e3e646a44 |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-1a4be39c57f54c89a10a613e3e646a442024-12-29T12:51:50ZengBMCActa Neuropathologica Communications2051-59602024-12-0112111510.1186/s40478-024-01912-xJMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory painXi-Biao He0Fang Guo1Wei Zhang2Jiacheng Fan3Weidong Le4Qi Chen5Yongjun Ma6Yong Zheng7Sang-Hun Lee8Hui-Jing Wang9Yi Wu10Qinming Zhou11Rui Yang12Laboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesLaboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesState Key Laboratory of Microbial Metabolism, School of Life Science and Biotechnology, Shanghai Jiao Tong UniversityLaboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesCenter for Translational Medicine, Shanghai University of Medicine & Health SciencesLaboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesLaboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesLaboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesDepartment of Biochemistry and Molecular Biology, College of Medicine, Hanyang UniversityLaboratory of Neuropsychopharmacology, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesLaboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesDepartment of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineLaboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health SciencesAbstract Midbrain dopamine (mDA) neurons participate in a wide range of brain functions through an intricate regulation of DA biosynthesis. The epigenetic factors and mechanisms in this process are not well understood. Here we report that histone demethylase JMJD3 is a critical regulator for DA biosynthesis in adult mouse mDA neurons. Mice carrying Jmjd3 conditional knockout or undergoing pharmaceutical inhibition of JMJD3 showed consistent reduction of DA content in midbrain and striatum. Histological examination of both mice confirmed that TH and NURR1, two key molecules in DA biosynthesis pathway, were decreased in mDA neurons. Mechanistic experiments in vivo and in vitro further demonstrated that the transcriptions of Th and Nurr1 in mDA neurons were suppressed by JMJD3 deficiency, because of increased repressive H3K27me3 and attenuated bindings of JMJD3 and NURR1 on the promoters of both genes. On behavioral level, a significant prolonged inflammation-induced mechanical hyperalgesia was found in conditional knockout mice regardless of sex and age, whereas motor function appeared to be intact. Our findings establish a novel link between DA level in mDA neurons with intrinsic JMJD3 activity, and suggest prolonged chronic inflammatory pain as a major loss-of-function consequence.https://doi.org/10.1186/s40478-024-01912-xDopamine biosynthesisMidbrain dopamine neuronTranscriptional regulationChronic inflammatory painEpigenetic control |
| spellingShingle | Xi-Biao He Fang Guo Wei Zhang Jiacheng Fan Weidong Le Qi Chen Yongjun Ma Yong Zheng Sang-Hun Lee Hui-Jing Wang Yi Wu Qinming Zhou Rui Yang JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain Acta Neuropathologica Communications Dopamine biosynthesis Midbrain dopamine neuron Transcriptional regulation Chronic inflammatory pain Epigenetic control |
| title | JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain |
| title_full | JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain |
| title_fullStr | JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain |
| title_full_unstemmed | JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain |
| title_short | JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain |
| title_sort | jmjd3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain |
| topic | Dopamine biosynthesis Midbrain dopamine neuron Transcriptional regulation Chronic inflammatory pain Epigenetic control |
| url | https://doi.org/10.1186/s40478-024-01912-x |
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