Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1

Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.

MicroRNA expression profiles and functions in the brain

MicroRNAs are abundant in the brains of vertebrates and some show a brain-specific or brain-enriched expression pattern. Because microRNAs regulate the expression of hundreds of target genes, it is not surprising that they have profoundly important functions in brain development and pathological processes. For example, miR-124 plays an important role in inducing and maintaining neuronal identity through targeting at least two anti-neural factors. MicroRNAs have also been implicated in brain disorders, including brain tumors and neurodegenerative diseases. This review aims to present an overview of the expression profiles and functions of microRNAs in the developing brains of vertebrates.

LC2 and OsVIL2 Promote Rice Flowering by Photoperoid-lnduced Epigenetic Silencing of OsLF

Proper flowering time is essential for plant reproduction. Winter annual Arabidopsis thaliana needs ver-nalization before flowering, during which AtVILs （VIN3 and VRNS, components of PRC2 complex） mediate the H3K27 tri- methylation at the FLC locus （a floral repressor） to repress the FLC expression and hence to induce flowering. However, how VILs （VIL, VERNALIZATION INSENSITIVE 3-LIKE） function in rice is unknown. Here we demonstrated that rice LC2 （OsVIL3） and OsVIL2 （two OsVILs, possible components of PRC2 complex） promote rice flowering. Our results showed that expressions of LC2 and OsVIL2 are induced by SD （short-day） conditions and both Ic2 mutant and OsVIL2-RNAi lines display delayed heading date, consistent with the reduced expression levels of Hdl and Hd3a. Interestingly, LC2 binds to the promoter region of a floral repressor OsLF and represses the OsLF expression via H3K27 tri-methylation modification. In addition, OsLF directly regulates the Hdl expression through binding to Hdl promoter. These results first demonstrated that the putative PRC2 in rice is involved in photoperiod flowering regulation, which is different from that of Arabidopsis, and revealed that LC2 binds the promoter region of target gene, presenting a possible mechanism of the recruitment pro-cess of PRC2 complex to its target genes. The studies provide informative clues on the epigenetic control of rice flowering.