OBJECTIVE: To explore the role of nuclear receptor-binding SET-domain protein 1 (NSD1) in the pathogenesis of nonobstructive azoospermia (NOA) by regulating the expressions of relevant genes. METHODS: We detected the expression of NSD1 in the testis tissue of 7 male patients with obstructive azoospermia (OA) and 18 with NOA by qPCR and immunofluorescence assay, and determined the modification level of H3K36me2 in the testes of two groups of patients by immunofluorescence staining, Western blot and immunoprecipitation (IP). We examined the difference in the enrichment of H3K36me2 in the testis tissue by chromatin IP-based sequencing (ChIP-Seq), analyzed the genomic distribution and target genes using bioinformatics, and verified the expression levels of the target genes in the testes of the two groups of patients by qPCR. RESULTS: Compared with the patients with OA, those with NOA showed dramatically decreased mRNA and protein expressions of NSD1 (P=0.000 8). The binding of NSD1 to H3K36me2 was observed in the testis tissue of both the two groups of patients, while the modification level of H3K36me2 was evidently reduced in the NOA males. H3K36me2 was distributed mainly in the intergenic region in the testes of the two groups of patients, but the enrichment of H3K36me2 was obviously decreased in the NOA group. The differentially H3K36me2-enriched genes were involved in various biological processes, including tissue development, and cell morphogenesis. Results of ChIP-Seq and qPCR showed significantly down-regulated expressions of the target genes KIT, SPO11 and ACRV1 in the testis tissue of the NOA males compared with those in the OA patients (P<0.01). CONCLUSION The levels of NSD1 and H3K36me2 are decreased in testis tissue of the NOA patient, H3K36me2 is highly enriched in the spermatogenesis-related key genes KIT, SPO11 and ACRV1, and the down-regulated expression of NSD1 impairs spermatogenesis.
Humans ; Male ; Azoospermia/genetics* ; Testis/metabolism* ; Histone-Lysine N-Methyltransferase/metabolism* ; Histones/metabolism*

Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis. However, mechanisms associated with stem cell senescence require further investigation. In this study, we conducted a proteomic analysis of human dental pulp stem cells (HDPSCs) obtained from individuals of various ages. Our findings showed that the expression of NUP62 was decreased in aged HDPSCs. We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo. Conversely, the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs. Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression, we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1. This, in turn, stimulates the transcription of the epigenetic enzyme NSD2. Finally, the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes (HMGA1, HMGA2, and SIRT6). Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.
Humans ; Dental Pulp/cytology* ; Nuclear Pore Complex Proteins/genetics* ; Cellular Senescence/genetics* ; Stem Cells/metabolism* ; Epigenesis, Genetic ; Cell Proliferation ; Cell Differentiation ; Histone-Lysine N-Methyltransferase/metabolism* ; Cells, Cultured ; Cellular Reprogramming ; Cell Movement ; Proteomics

Successful cloning through somatic cell nuclear transfer (SCNT) faces significant challenges due to epigenetic obstacles. Recent studies have highlighted the roles of H3K4me3 and H3K27me3 as potential contributors to these obstacles. However, the underlying mechanisms remain largely unclear. In this study, we generated genome-wide maps of H3K4me3 and H3K27me3 in mouse pre-implantation NT embryos. Our analysis revealed that aberrantly over-represented broad H3K4me3 domain and H3K27me3 signal lead to increased bivalent marks at gene promoters in NT embryos compared with naturally fertilized (NF) embryos at the 2-cell stage, which may link to relatively low levels of H3K36me3 in NT 2-cell embryos. Notably, the overexpression of Setd2, a H3K36me3 methyltransferase, successfully restored multiple epigenetic marks, including H3K36me3, H3K4me3, and H3K27me3. In addition, it reinstated the expression levels of ZGA-related genes by reestablishing H3K36me3 at gene body regions, which excluded H3K27me3 from bivalent promoters, ultimately improving cloning efficiency. These findings highlight the excessive bivalent state at gene promoters as a potent barrier and emphasize the removal of these barriers as a promising approach for achieving higher cloning efficiency.
Animals ; Mice ; Histone-Lysine N-Methyltransferase/biosynthesis* ; Histones/genetics* ; Nuclear Transfer Techniques ; Female ; Gene Expression Regulation, Developmental ; Promoter Regions, Genetic ; Epigenesis, Genetic ; Embryo, Mammalian/metabolism*

The p60 subunit of the chromatin assembly factor-1 complex, that is, chromatin assembly factor-1 subunit B (CHAF1B), is a histone H3/H4 chaperone crucial for the transcriptional regulation of cell differentiation and self-renewal. CHAF1B is overexpressed in several cancers and may represent a potential target for cancer therapy. However, its expression and clinical significance in lung squamous-cell carcinoma (LUSC) remain unclear. In this study, we performed weighted gene correlation network analysis to analyze the Gene Expression Omnibus GSE68793 LUSC dataset and identified CHAF1B as one of the most important driver gene candidates. Immunohistochemical analysis of 126 LUSC tumor samples and 80 adjacent normal lung tissues showed the marked upregulation of CHAF1B in tumor tissues and the negative association of its expression level with patient survival outcomes. Silencing of CHAF1B suppressed LUSC proliferation in vitro and LUSC tumor growth in vivo. Furthermore, bulk RNA sequencing of CHAF1B knockdown cells indicated SET domain containing 7 (SETD7) as a significant CHAF1B target gene. In addition, CHAF1B competitively binds to the SETD7 promoter region and represses its transcription. Altogether, these results imply that CHAF1B plays a vital role in LUSC tumorigenesis and may represent a potential molecular target for this deadly disease.
Humans ; Lung Neoplasms/metabolism* ; Histone-Lysine N-Methyltransferase/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Gene Expression Regulation, Neoplastic ; Disease Progression ; Cell Proliferation/genetics* ; Cell Line, Tumor ; Chromatin Assembly Factor-1/metabolism* ; Animals ; Mice ; Male ; Female

Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs' roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.
Nucleosomes ; Histones/metabolism* ; Histone-Lysine N-Methyltransferase/metabolism* ; Lysine/metabolism* ; Methyltransferases/metabolism* ; Methylation

The occurence and development of tumors is a complicated process, which not only depends on the mutation or deletion of genes, but also is affected by epigenetic regulation. Accumulating evidences have shown that epigenetic modifications play fundamental roles in transcriptional regulation, heterochromatin formation, X chromosome inactivation, DNA damage response and tumor development. SET domain containing lysine methyltransferase 7 (SETD7) was initially identified as an important lysine methyltransferase, which methylated histone and non-histone proteins. These modifications play fundamental roles. Once this modification disorders, it can directly lead to cell abnormalities and cause many diseases. Studies have shown that SETD7 is related to the occurence and development of various tumors, but the methylation sites of SETD7 and its regulatory mechanism have not been fully elucidated. This article summarizes the research progress of the role of SETD7 on histone and non-histone methylation modification in tumors and the molecular mechanism, in order to provide new therapeutic targets for tumor pathogenesis and diagnosis.
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Humans ; Epigenesis, Genetic ; Histone-Lysine N-Methyltransferase/metabolism* ; Lysine/metabolism* ; Lung Neoplasms/genetics* ; Histones/metabolism*

OBJECTIVES: Our previous study has verified that high level of SET and MYND domain-containing protein 2 (SMYD2) plays an important role in acquiring aggressive ability for liver cancer cells in hepatocellular carcinoma. MiR-200b as a tumor suppressor gene involves in a variety of cancers. This study aims to investigate the correlation between miR-200b and SMYD2 in hepatocellular carcinoma and the underlying mechanism. METHODS: Firstly, the levels of SMYD2 and miR-200b in hepatocellular carcinoma tissues and matched adjacent non-tumor liver tissues were tested with real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Secondly, we evaluated the interaction between miR-200b and SMYD2 using dual-luciferase reporter assay. Thirdly, we elucidated the effect of miR-200b on SMYD2 and its downstream targets p53/CyclinE1. Finally, we silenced SMYD2 in hepatocellular carcinoma cell lines to investigate its effect on tumor proliferation and cell cycle progression, and further confirmed the correlation among SMYD2 and p53/CyclinE1. RESULTS: Compared with the matched adjacent non-tumor liver tissues, miR-200b was obviously decreased, and SMYD2 was significantly increased in hepatocellular carcinoma (both P<0.05). Spearman's rank correlation revealed that miR-200b expression was negatively correlated with SMYD2 (P<0.01). Computer algorithm and dual-luciferase reporter assay revealed that miR-200b directly targeted and suppressed SMYD2 in HEK 293T cells. The down-regulated miR-200b expression promoted hepatoma cell proliferation (P<0.05) and increased SMYD2 expression(P<0.01), while the up-regulated expression of miR-200b had an opposite effect. The knockdown of SMYD2 suppressed the proliferation of MHCC-97L cells (P<0.01), down-regulated CyclinE1, and up-regulated p53 expression (both P<0.05). CONCLUSIONS MiR-200b is involved in hepatocellular carcinoma progression via targeting SMYD2 and regulating SMYD2/p53/CyclinE1 signaling pathway and may be used as a potential target for hepatocellular carcinoma treatment.
Humans ; Carcinoma, Hepatocellular/pathology* ; Tumor Suppressor Protein p53/metabolism* ; MicroRNAs/metabolism* ; Cell Line, Tumor ; Signal Transduction ; Liver Neoplasms/pathology* ; Cell Proliferation/genetics* ; Histone-Lysine N-Methyltransferase/metabolism*

Traumatic brain injury (TBI) contributes to the key causative elements of neurological deficits. However, no effective therapeutics have been developed yet. In our previous work, extracellular vesicles (EVs) secreted by stem cells from human exfoliated deciduous teeth (SHED) offered new insights as potential strategies for functional recovery of TBI. The current study aims to elucidate the mechanism of action, providing novel therapeutic targets for future clinical interventions. With the miRNA array performed and Real-time PCR validated, we revealed the crucial function of miR-330-5p transferred by SHED-derived EVs (SHED-EVs) in regulating microglia, the critical immune modulator in central nervous system. MiR-330-5p targeted Ehmt2 and mediated the transcription of CXCL14 to promote M2 microglia polarization and inhibit M1 polarization. Identified in our in vivo data, SHED-EVs and their effector miR-330-5p alleviated the secretion of inflammatory cytokines and resumed the motor functional recovery of TBI rats. In summary, by transferring miR-330-5p, SHED-EVs favored anti-inflammatory microglia polarization through Ehmt2 mediated CXCL14 transcription in treating traumatic brain injury.
Animals ; Brain Injuries, Traumatic/therapy* ; Chemokines, CXC/metabolism* ; Extracellular Vesicles/metabolism* ; Histocompatibility Antigens/metabolism* ; Histone-Lysine N-Methyltransferase/metabolism* ; Humans ; MicroRNAs/metabolism* ; Microglia/metabolism* ; Rats ; Stem Cells/metabolism*

Cancer metabolism is considered as one of major cancer hallmarks. It is important to understand cancer-specific metabolic changes and its impact on cancer biology to identify therapeutic potentials. Among cancer-specific metabolic changes, a role of serine metabolism has been discovered in various cancer types. Upregulation of serine synthesis pathway (SSP) supports cell proliferation and metastasis. The change of serine metabolism is, in part, mediated by epigenetic modifiers, such as Euchromatic histone-lysine N-methyltransferase 2 and Lysine Demethylase 4C. On the other hand, SSP also influences epigenetic landscape such as methylation status of nucleic acids and histone proteins via affecting S-adenosyl methionine production. In the review, we highlight recent evidences on interactions between SSP and epigenetic regulation in cancer. It may provide an insight on roles and regulation of SSP in cancer metabolism and the potential of serine metabolism for cancer therapy.
Biology ; Cell Proliferation ; Epigenomics* ; Hand ; Histone-Lysine N-Methyltransferase ; Histones ; Lysine ; Metabolism* ; Methionine ; Methylation ; Neoplasm Metastasis ; Nucleic Acids ; Serine* ; Up-Regulation

No abstract available.
Adult ; Antigens, CD4/*metabolism ; Antigens, CD56/*metabolism ; Bone Marrow/metabolism/pathology ; Dendritic Cells/cytology/*metabolism ; Diagnostic Errors ; Exons ; Female ; Flow Cytometry ; Gene Rearrangement ; Hematologic Neoplasms/diagnosis ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Leukemia, Myeloid, Acute/*diagnosis ; Male ; Middle Aged ; Myeloid-Lymphoid Leukemia Protein/genetics ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Transcription Factors/genetics ; Translocation, Genetic