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.

Molecular evolutionary analysis of gene families encoding DNA recombination and repair proteins and histone demethylases,and their functional implications

Many eukaryotic genes are members of multi-gene families due to gene duplications, which generate new copies that allow functional divergence. However, the relationship between

Histone methyltransferases and demethylases:regulators in balancing osteogenic and adipogenic differentiation of mesenchymal stem cells

Mesenchymal stem cells （MSCs） are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su（var）3-9, enhancer-of-zeste, trithorax （SET） domain-containing family and the Jumonji C （JmjC） domain-containing family represent the major histone lysine methyltransferases （KMTs） and histone lysine demethylases （KDMs）, respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containine KMTs and JmiC domain-containinlz KDMs balance the osteogenic and adipogenic differentiation of MSCs.

Lysine-specific demethylase 1 expression in zebrafish during the early stages of neuronal development

Lysine-specific demethylase 1 （Lsdl） is associated with transcriptional coregulation via the modulation of histone methylation. The expression pattern and function of zebrafish Lsdl has not, however, been studied. Here, we describe the pattern of zebrafish Lsdl expression during different development stages. In the zebrafish embryo, Isdl mRNA was present during the early cleavage stage, indicating that maternally derived Lsdl protein is involved in embryonic patterning. During embryogenesis from 0 to 48 hours post-fertilization （hpf）, the expression of Isdl mRNA in the embryo was ubiquitous before 12 hpf and then became restricted to the antedor of the embryo （particularly in the brain） from 24 hpf to 72 hpf. Inhibition of Lsdl activity （by exposure to tranylcypromine） or knockdown of Isdl expression （by morpholino antisense oligonucleotide injection） led to the loss of cells in the brain and to a dramatic downregulatJon of neural genes, including gad65, gad75, and reelin, but not hey1. These findings indicate an important role of Lsdl during nervous system development in zebrafish.

Promising natural lysine specific demethylase 1 inhibitors for cancer treatment:advances and outlooks

Lysine specific demethylase 1(LSD1),a transcriptional corepressor or coactivator that serves as a demethylase of histone 3 lysine 4 and 9,has become a potential therapeutic target for cancer therapy.LSD1 mediates many cellular signaling pathways and regulates cancer cell proliferation,invasion,migration,and differentiation.Recent research has focused on the exploration of its pharmacological inhibitors.Natural products are a major source of compounds with abundant scaffold diversity and structural complexity,which have made a major contribution to drug discovery,particularly anticancer agents.In this review,we briefly highlight recent advances in natural LSD1 inhibitors over the past decade.We present a comprehensive review on their discovery and identification process,natural plant sources,chemical structures,anticancer effects,and structure-activity relationships,and finally provide our perspective on the development of novel natural LSD1 inhibitors for cancer therapy.

Natural products as LSD1 inhibitors for cancer therapy

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase1(LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.