LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1α expression

Abstract

Background Microglia-mediated neuroinflammation plays an important role in Parkinson’s disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD. Methods In our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization. Results We found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α. Conclusions Our findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD.

Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

“…M2 marker Arg1, a direct downstream target of Jmjd3, could partly reduce the harmful effects and exert neuroprotection effects as Jmjd3 is suppressed, acting as a critical neuron-survival molecule ( Tang et al, 2014 ). Long non-coding RNAs (lncRNAs) can regulate the function of target genes through epigenetic mechanisms as well, and are involved in the progression of neurodegenerative diseases ( Yang et al, 2021 ). HOXA cluster antisense RNA 2 (HOXA-AS2), one of the most abundantly expressed lncRNAs, was found upregulated in PD patients ( Yang et al, 2021 ).…”

“…Long non-coding RNAs (lncRNAs) can regulate the function of target genes through epigenetic mechanisms as well, and are involved in the progression of neurodegenerative diseases ( Yang et al, 2021 ). HOXA cluster antisense RNA 2 (HOXA-AS2), one of the most abundantly expressed lncRNAs, was found upregulated in PD patients ( Yang et al, 2021 ). Upregulated HOXA-AS2 promotes neuroinflammation by regulating microglia polarization through interacting with polycomb repressive complex 2 (PRC2) and epigenetically silencing PGC-1α in PD.…”

“…Upregulated HOXA-AS2 promotes neuroinflammation by regulating microglia polarization through interacting with polycomb repressive complex 2 (PRC2) and epigenetically silencing PGC-1α in PD. HOXA-AS2 knockdown could significantly repress microglia M1 polarization and promote M2 polarization ( Yang et al, 2021 ).…”

The Role of Non-Coding RNAs in the Pathogenesis of Parkinson’s Disease: Recent Advancement

“…HOXA-AS2 was considerably upregulated in peripheral blood mononuclear cells of patients with PD and showed a reversible regulatory relationship with PGC-1α expression. HOXA-AS2 promotes neuroinflammation by accelerating the conversion of microglia to an anti-inflammatory M2 phenotype [ 41 ].…”

LncRNA, an Emerging Approach for Neurological Diseases Treatment by Regulating Microglia Polarization

“…H19 knockdown drives histone deacetylase inhibitor (HDAC1), which inhibits M1 microglia and exerts neuroprotective effects ( Han et al, 2018b ). The lncRNA HOXA-AS2 can contribute to microglia M1 polarization by interacting with the polycomb repressor complex 2 complex and downregulating proliferator-activated receptor γ coactivator (PGC-1α) ( Yang et al, 2021 ) ( Figure 2 ).…”