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JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain
Xi-Biao He1, Fang Guo2, Wei Zhang3
1Laboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Highway, Pudong New Area, Shanghai, 201318, China. hexb@sumhs.edu.cn.
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.
Insights
Histone demethylase JMJD3 regulates dopamine (DA) biosynthesis in midbrain dopamine (mDA) neurons. JMJD3 deficiency reduces DA levels and prolongs pain, impacting brain function.
Area of Science:
- Neuroscience
- Epigenetics
- Molecular Biology
Background:
- Midbrain dopamine (mDA) neurons regulate crucial brain functions via dopamine (DA) biosynthesis.
- Epigenetic mechanisms controlling DA biosynthesis in mDA neurons remain largely uncharacterized.
Purpose of the Study:
- To investigate the role of histone demethylase JMJD3 in regulating DA biosynthesis in adult mouse mDA neurons.
- To elucidate the molecular mechanisms underlying JMJD3's function in mDA neurons.
Main Methods:
- Conditional knockout of Jmjd3 in adult mice.
- Pharmacological inhibition of JMJD3.
- Measurement of DA content in midbrain and striatum.
- Histological analysis of TH and NURR1 expression.
- In vivo and in vitro mechanistic studies on gene transcription and epigenetic modifications.
- Behavioral tests for pain and motor function.
Main Results:
- Jmjd3 deficiency led to reduced DA content in the midbrain and striatum.
- Expression of TH and NURR1 was decreased in mDA neurons of knockout mice.
- JMJD3 deficiency suppressed Th and Nurr1 transcription due to increased H3K27me3 and reduced JMJD3/NURR1 binding at gene promoters.
- Conditional knockout mice exhibited prolonged inflammation-induced mechanical hyperalgesia, while motor function remained unaffected.
Conclusions:
- Histone demethylase JMJD3 is a critical regulator of DA biosynthesis in adult mDA neurons.
- JMJD3 deficiency impairs DA homeostasis and leads to chronic inflammatory pain as a consequence of DA level reduction.
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