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Extracellular vesicles from skin-derived precursor Schwann cells (SKP-SC-EVs) promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats. This study aimed at expanding the application of SKP-SC-EVs in nerve grafting by creating a chitosan/PLGA-based, SKP-SC-EVs-containing tissue engineered nerve graft (TENG) to bridge a 40-mm long sciatic nerve defect in dogs. SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions, supported the outgrowth and myelination of regenerated axons, and alleviated the denervation-induced atrophy of target muscles in dogs. To clarify the underlying molecular mechanism, we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons, and miR-30b-5p was the most important among others. We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK, STAT3 or CREB. Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic. [Display omitted] •Chitosan/PLGA-based, SKP-SC-EVs-containing tissue engineered nerve grafts were developed as novel bioactive materials.•Our-developed nerve grafts significantly enhanced sciatic nerve regeneration across a long defect in dogs.•SKP-SC-EVs presented exosome-based cell-free therapies for peripheral nerve repair through delivering biological cues.•Various highly expressed miRNAs in SKP-SC-EVs were involved in axon growth and motor or cortical neuron regeneration.•miR-30b-5p played a key role by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK, STAT3 or CREB.

Long noncoding RNAs (lncRNAs) are increasingly recognized as key regulators of lung adenocarcinoma (LUAD), yet for many lncRNAs the upstream repressors and downstream effector pathways remain unclear. Here, we identify MIR22HG as a frequently downregulated lncRNA in LUAD, and show that its low expression is associated with aggressive tumor behavior and poor clinical outcome. Functionally, MIR22HG restrains LUAD progression, as evidenced by reduced proliferation, migration, invasion, and xenograft growth upon MIR22HG restoration. Mechanistically, MIR22HG promotes Beclin1-associated autophagy and ferroptosis, providing a functional basis for its tumor-suppressive activity. We further demonstrate that SIN3A serves as an RNA-binding protein that negatively regulates MIR22HG at the post-transcriptional level. SIN3A depletion increases MIR22HG abundance, enhances autophagy- and ferroptosis-related signaling, and suppresses malignant phenotypes in LUAD cells. Importantly, genetic rescue experiments indicate that these SIN3A-dependent effects are partially mediated through MIR22HG, supporting a functional SIN3A–MIR22HG regulatory relationship. Collectively, our data delineate an SIN3A–MIR22HG–Beclin1 regulatory axis that links RNA-level repression to autophagy and ferroptosis control in LUAD and suggest that disruption of this pathway contributes to tumor progression. Targeting SIN3A-mediated repression of MIR22HG may, therefore, represent a potential therapeutic avenue for LUAD. Highlights MIR22HG is significantly downregulated in LUAD and functions as a tumor suppressor. MIR22HG activates both autophagy and ferroptosis via Beclin1-mediated signaling. SIN3A directly binds and represses MIR22HG, inhibiting autophagy and ferroptosis. Silencing SIN3A promotes autophagy and ferroptosis and suppresses LUAD progression. Targeting the SIN3A/MIR22HG/Beclin1 axis offers potential therapeutic strategies.

PurposeBerberine chloride (BBC) is a well-known plant isoquinoline alkaloid derived from Berberis aristata. In this study, we aim to explore the effect of BBC on non-small cell lung cancer (NSCLC), and further expound the underlying mechanism of BBC induces NSCLC cell death in vitro and in vivo.MethodsCCK-8 assay and colony formation assay were used to test the viability and colony formation ability of NSCLC cells. Apoptosis analysis was used to analyze the apoptotic cells. siRNAs were utilized to disturb the expression of Sin3A. qPCR and Western blot analysis were employed to determine mRNA and protein levels of related genes and proteins. Tumor xenografts model was used for in vivo detection.ResultsBBC inhibited the proliferation and colony formation of human NSCLC cells in a dose- and time-dependent manner. In addition, BBC induced DNA double-stranded breaks (DSBs) through downregulating TOP2B level, leading to apoptosis in human NSCLC cells. The Chip-seq data of A549 cells obtained from the ENCODE consortium indicate that Sin3A binds on the promoters of TOP2B. Knockdown of Sin3A led to downregulation of TOP2B in human NSCLC cells. Furthermore, BBC decreased Sin3A expression and shortened the half-life of Sin3A, results in downregulation of TOP2B in human NSCLC cells.ConclusionIn this study, we demonstrated a new mechanism that BBC suppresses human NSCLC by deregulating Sin3A/TOP2B pathway, leading to DNA damage and apoptosis in human NSCLC in vitro and in vivo.

Background Reduction of histone deacetylase (HDAC) 2 expression and activity may contribute to amplified inflammation in patients with severe asthma. Connective tissue growth factor (CTGF) is a key mediator of airway fibrosis in severe asthma. However, the role of the HDAC2/Sin3A/methyl-CpG-binding protein (MeCP) 2 corepressor complex in the regulation of CTGF expression in lung fibroblasts remains unclear. Methods The role of the HDAC2/Sin3A/MeCP2 corepressor complex in endothelin (ET)-1-stimulated CTGF production in human lung fibroblasts (WI-38) was investigated. We also evaluated the expression of HDAC2, Sin3A and MeCP2 in the lung of ovalbumin-induced airway fibrosis model. Results HDAC2 suppressed ET-1-induced CTGF expression in WI-38 cells. ET-1 treatment reduced HDAC2 activity and increased H3 acetylation in a time-dependent manner. Furthermore, overexpression of HDAC2 inhibited ET-1-induced H3 acetylation. Inhibition of c-Jun N-terminal kinase, extracellular signal-regulated kinase, or p38 attenuated ET-1-induced H3 acetylation by suppressing HDAC2 phosphorylation and reducing HDAC2 activity. Overexpression of both Sin3A and MeCP2 attenuated ET-1-induced CTGF expression and H3 acetylation. ET-1 induced the disruption of the HDAC2/Sin3A/MeCP2 corepressor complex and then prompted the dissociation of HDAC2, Sin3A, and MeCP2 from the CTGF promoter region. Overexpression of HDAC2, Sin3A, or MeCP2 attenuated ET-1-stimulated AP-1-luciferase activity. Moreover, Sin3A- or MeCP2-suppressed ET-1-induced H3 acetylation and AP-1-luciferase activity were reversed by transfection of HDAC2 siRNA. In an ovalbumin-induced airway fibrosis model, the protein levels of HDAC2 and Sin3A were lower than in the control group; however, no significant difference in MeCP2 expression was observed. The ratio of phospho-HDAC2/HDAC2 and H3 acetylation in the lung tissue were higher in this model than in the control group. Overall, without stimulation, the HDAC2/Sin3A/MeCP2 corepressor complex inhibits CTGF expression by regulating H3 deacetylation in the CTGF promoter region in human lung fibroblasts. With ET-1 stimulation, the HDAC2/Sin3A/MeCP2 corepressor complex is disrupted and dissociated from the CTGF promoter region; this is followed by AP-1 activation and the eventual initiation of CTGF production. Conclusions The HDAC2/Sin3A/MeCP2 corepressor complex is an endogenous inhibitor of CTGF in lung fibroblasts. Additionally, HDAC2 and Sin3A may be of greater importance than MeCP2 in the pathogenesis of airway fibrosis.

T-regulatory (Treg) cells display considerable heterogeneity in their responses to various cancers. The functional differences among this cell type are heavily influenced by multiprotein nuclear complexes that control their gene expression. Many such complexes act mechanistically by altering epigenetic profiles of genes important to Treg function, including the forkhead P3 (Foxp3) transcription factor. Complexes that form with certain members of the histone/protein deacetylase (HDAC) class of enzymes, like HDACs 1, 2, and 3, along with histone methyltransferase complexes, are important in the induction and stabilization of Foxp3 and Treg identity. The functional behavior of both circulating and intratumoral Tregs greatly impacts the antitumor immune response and can be predictive of patient outcome. Thus, targeting these regulatory complexes within Tregs may have therapeutic potential, especially in personalized immunotherapies.

Background The expression of SIN3A is closely correlated with electroacupuncture (EA) treatment efficacy of scopolamine-induced amnesia (SIA), but its underlying mechanisms remain to be further explored. Methods Quantitative real-time PCR was performed to analyze the expression of candidate microRNAs (miRNAs) and SIN3A mRNA in a rat model of SIA. Western blot was carried out to evaluate the differential expression of SIN3A proteins under different circumstances. Luciferase assay was used to explore the inhibitory role of certain miRNAs in SIN3A expression. A novel object recognition (NOR) test was performed to assess the memory function of SIA rats undergoing EA treatment. Immunohistochemistry was carried out to evaluate the expression of SIN3A in the hippocampus of SIA rats. Results Rno-miR-183-5p, rno-miR-34c-3p and rno-miR-210-3p were significantly up-regulated in SIA rats treated with EA. In addition, rno-miR-183-5p and rno-miR-210-3p exerted an inhibitory effect on SIN3A expression. EA treatment of SIA rats effectively restored the dysregulated expression of rno-miR-183-5p, rno-miR-210-3p and SIN3A. EA treatment also promoted the inhibited expression of neuronal IEGs including Arc, Egr1, Homer1 and Narp in the hippocampus of SIA rats. Accordingly, the NOR test also confirmed the effect of EA treatment on the improvement of memory in SIA rats. Conclusion In summary, the findings of this study demonstrated that scopolamine-induced amnesia was associated with downregulated expression of miR-210/miR-183 and upregulated expression of SIN3A. Furthermore, treatment with EA alleviated scopolamine-induced amnesia in rats and was associated with upregulated expression of miR-210/miR-183 and downregulated expression of SIN3A.

Diabetic foot ulcers (DFUs) represent a severe complication of diabetes associated with reduced quality of life, lower limb amputations, hospitalizations, increased incidence, and mortality. Importantly, a significant number of pathogenic genes remain unexplored in DFUs. A series of bioinformatics analyses were performed on publicly available bulk transcriptome sequencing datasets GSE134431 and GSE80178 to explore the transcriptomic changes in DFUs and select core genes for in vitro functional validation. In a focused examination, the differential expression analysis unveiled distinctions in gene expression patterns between DFUs and non-ulcerated diabetic skin tissues. Enriched functional annotations of differentially expressed genes were explored using the DAVID online tool. Protein-protein interaction analysis was conducted to investigate interactions among differentially expressed genes and select core genes. Knockdown or overexpression of core genes in HaCaT keratinocytes was performed to assess their impact on cell proliferation and migration. Ten core genes were identified. Cell Counting Kit-8 (CCK-8) and scratch assays demonstrated that downregulation of the core gene SIN3A significantly inhibited the migration and proliferation of HaCaT keratinocytes, while overexpression of SIN3A reversed the high-glucose-induced suppression of HaCaT cell viability and migration. SIN3A expression is downregulated in DFUs. In vitro, SIN3A promotes the proliferation and migration of HaCaT keratinocytes, suggesting it may be a potential therapeutic target for DFUs.

IFI16 is a well-characterized nuclear innate immune DNA sensor that detects foreign dsDNA, including herpesviral genomes, to activate the inflammasome and interferon pathways. Beyond immune signaling, IFI16 also functions as an antiviral restriction factor, promoting the silencing of invading viral genes through transcriptional and epigenetic mechanisms. We recently demonstrated another role of IFI16, in which it interacts with and recruits the class I histone deacetylases, HDAC1 and 2, to the KSHV latency protein LANA, modulating its acetylation and function. In this study, we asked whether these IFI16-HDAC1/2 interactions contribute to broader epigenetic regulation of the KSHV chromatin. Our findings reveal that IFI16 associates with and facilitates the recruitment of the NuRD and Sin3A co-repressor complexes—both multiprotein, HDAC1/2-containing chromatin regulators—on KSHV episomes. Depletion of IFI16 led to reductions in NuRD and Sin3A occupancy on viral chromatin, accompanied by increased histone acetylation at lytic gene promoters. These results suggest that IFI16 plays a critical role in recruiting or stabilizing these HDAC-containing co-repressor complexes on the KSHV genome, thereby enforcing transcriptional silencing of lytic genes and maintaining latency in KSHV. Our study expands the known functions of IFI16 and identifies a novel epigenetic mechanism by which it modulates herpesviral chromatin states.

Histone deacetylases 1 and 2 play a major role in the transcriptional regulation of T-regulatory (Treg) cells via interactions with a myriad of coregulatory factors. Sin3a has been well established as a Hdac1/2 cofactor, while its role within Tregs has not been established. In this study, the effects of conditional deletion of Sin3a within Foxp3+ Tregs were evaluated. Developmental deletion of Sin3a from Foxp3+ Tregs resulted in the rapid onset of fatal autoimmunity. Treg numbers were greatly reduced, while residual Tregs had impaired suppressive function. Mice also showed effector T-cell activation, autoantibody production, and widespread tissue injury. Mechanistically, Sin3a deletion resulted in decreased transcription of Foxp3 with a complete lack of CNS2 CpG demethylation. In addition, Foxp3 protein stability was impaired with an increased ex-Treg population. Thus, Sin3a plays a critical role in the maintenance of Treg identity and function and is essential for the expression and stability of Foxp3.

Background Colorectal cancer (CRC) is a malignant tumor affecting people worldwide. Long noncoding RNAs (lncRNAs) is a crucial factor modulating various cancer progression, including CRC. Long intergenic non-protein coding RNA 665 (LINC00665) has been proven as an oncogene in several cancers, but its function in CRC is still unclear. Methods QRT-PCR was performed for RNA quantification. Functional assays were designed and carried to test cell phenotype while mechanism experiments were adopted for detecting the interaction of LINC00665, microRNA-138-5p (miR-138-5p) and SIN3 transcription regulator family member A (SIN3A). In vivo experiments were conducted to test LINC00665 function on modulating CRC tumor progression. Results LINC00665 displayed high expression in CRC tissues and cells, and promoted tumor progression in vivo. MiR-138-5p displayed abnormally low expression in CRC, and was verified to be sponged by LINC00665. Furthermore, SIN3A, as the downstream mRNA of miR-138-5p, exerted promoting impacts on CRC cells. Rescue experiments certified that overexpressed SIN3A or silenced miR-138-5p could offset the repressed function of LINC00665 knockdown on CRC progression. Conclusions LINC00665 could sponge miR-138-5p to up-regulate SIN3A expression, thus accelerating CRC progression. Graphic abstract