The up-regulation of SYNCRIP promotes the proliferation and tumorigenesis via DNMT3A/p16 in colorectal cancer.

Heterogeneous nuclear ribonucleoproteins (hnRNPs), a group of proteins that control gene expression, have been implicated in many post-transcriptional processes. SYNCRIP (also known as hnRNP Q), a subtype of hnRNPs, has been reported to be involved in mRNA splicing and translation. In addition, the deregulation of SYNCRIP was found in colorectal cancer (CRC). However, the role of SYNCRIP in regulating CRC growth remains largely unknown. Here, we found that SYNCRIP was highly expressed in colorectal cancer by analyzing TCGA and GEPIA database. Furthermore, we confirmed the expression of SYNCRIP expression in CRC tumor and CRC cell lines. Functionally, SYNCRIP depletion using shRNA in CRC cell lines (SW480 and HCT 116) resulted in increased caspase3/7 activity and decreased cell proliferation, as well as migration. Meanwhile, overexpression of SYNCRIP showed opposite results. Mechanistically, SYNCRIP regulated the expression of DNA methyltransferases (DNMT) 3A, but not DNMT1 or DNMT3B, which affected the expression of tumor suppressor, p16. More importantly, our in vivo experiments showed that SYNCRIP depletion significantly inhibited colorectal tumor growth. Taken all together, our results suggest SYNCRIP as a potent therapeutic target in colorectal cancer.

Dynamically adjusted cell fate decisions and resilience to mutant invasion during steady-state hematopoiesis revealed by an experimentally parameterized mathematical model.

A major next step in hematopoietic stem cell (HSC) biology is to enhance our quantitative understanding of cellular and evolutionary dynamics involved in undisturbed hematopoiesis. Mathematical models have been and continue to be key in this respect, and are most powerful when parameterized experimentally and containing sufficient biological complexity. In this paper, we use data from label propagation experiments in mice to parameterize a mathematical model of hematopoiesis that includes homeostatic control mechanisms as well as clonal evolution. We find that nonlinear feedback control can drastically change the interpretation of kinetic estimates at homeostasis. This suggests that short-term HSC and multipotent progenitors can dynamically adjust to sustain themselves temporarily in the absence of long-term HSCs, even if they differentiate more often than they self-renew in undisturbed homeostasis. Additionally, the presence of feedback control in the model renders the system resilient against mutant invasion. Invasion barriers, however, can be overcome by a combination of age-related changes in stem cell differentiation and evolutionary niche construction dynamics based on a mutant-associated inflammatory environment. This helps us understand the evolution of e.g., TET2 or DNMT3A mutants, and how to potentially reduce mutant burden.

Structural insight into the DNMT1 reaction cycle by cryo-electron microscopy.

DNMT1 is an essential DNA methyltransferase that catalyzes the transfer of methyl groups to CpG islands in DNA and generates a prominent epigenetic mark. The catalytic activity of DNMT1 relies on its conformational plasticity and ability to change conformation from an auto-inhibited to an activated state. Here, we present four cryo-EM reconstructions of apo DNMT1 and DNTM1: non-productive DNA, DNTM1: H3Ub2-peptide, DNTM1: productive DNA complexes. Our structures demonstrate the flexibility of DNMT1's N-terminal regulatory domains during the transition from an apo 'auto-inhibited' to a DNA-bound 'non-productive' and finally a DNA-bound 'productive' state of DNMT1. Furthermore, we address the regulation of DNMT1's methyltransferase activity by a DNMT1-selective small-molecule inhibitor and ubiquitinated histone H3. We observe that DNMT1 binds DNA in a 'non-productive' state despite the presence of the inhibitor and present the cryo-EM reconstruction of full-length DNMT1 in complex with a di-ubiquitinated H3 peptide analogue. Taken together, our results provide structural insights into the reaction cycle of DNMT1.

Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis.

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CHIP. Splicing factor genes (SF3B1, SRSF2, U2AF1, and ZRSR2) and TET2 CHIP grow significantly faster than DNMT3A non-R882 clones. We find that age at baseline and sex significantly influence the incidence of CHIP, while ASCVD and other traditional ASCVD risk factors do not exhibit such associations. Additionally, baseline synonymous passenger mutations are strongly associated with CHIP status and are predictive of new CHIP clone acquisition and clonal growth over extended follow-up, providing valuable insights into clonal dynamics of aging hematopoietic stem and progenitor cells. This study also reveals associations between germline genetic variants and incident CHIP. Our comprehensive longitudinal assessment yields insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.

Molecular mechanisms for DNA methylation defects induced by ICF syndrome-linked mutations in DNMT3B.

DNA methyltransferase 3B (DNMT3B) plays a crucial role in DNA methylation during mammalian development. Mutations in DNMT3B are associated with human genetic diseases, particularly immunodeficiency, centromere instability, facial anomalies (ICF) syndrome. Although ICF syndrome-related missense mutations in the DNMT3B have been identified, their precise impact on protein structure and function remains inadequately explored. Here, we delve into the impact of four ICF syndrome-linked mutations situated in the DNMT3B dimeric interface (H814R, D817G, V818M, and R823G), revealing that each of these mutations compromises DNA-binding and methyltransferase activities to varying degrees. We further show that H814R, D817G, and V818M mutations severely disrupt the proper assembly of DNMT3B homodimer, whereas R823G does not. We also determined the first crystal structure of the methyltransferase domain of DNMT3B-DNMT3L tetrameric complex hosting the R823G mutation showing that the R823G mutant displays diminished hydrogen bonding interactions around T775, K777, G823, and Q827 in the protein-DNA interface, resulting in reduced DNA-binding affinity and a shift in sequence preference of +1 to +3 flanking positions. Altogether, our study uncovers a wide array of fundamental defects triggered by DNMT3B mutations, including the disassembly of DNMT3B dimers, reduced DNA-binding capacity, and alterations in flanking sequence preferences, leading to aberrant DNA hypomethylation and ICF syndrome.

SOX7 inhibits the malignant progression of bladder cancer via the DNMT3B/CYGB axis.

Bladder cancer (BCa) stands out as a highly prevalent malignant tumor affecting the urinary system. The Sex determining region Y-box protein family is recognized for its crucial role in BCa progression. However, the effect of Sex determining region Y-box 7 (SOX7) on BCa progression has not been fully elucidated. Herein, RNA-sequencing, western blot (WB), immunohistochemistry (IHC), immunofluorescence (IF) and tissue microarray were utilized to assess SOX7 expression in vitro and in vivo. Additionally, SOX7 expression, prognosis, and SOX7 + cytoglobin (CYGB) score were analyzed using R software. In vitro and vivo experiments were performed with BCa cell lines to validate the effect of SOX7 knockdown and overexpression on the malignant progression of BCa. The results showed that SOX7 exhibits low expression in BCa. It functions in diverse capacities, inhibiting the proliferative, migratory, and invasive capabilities of BCa. In addition, the experimental database demonstrated that SOX7 binds to the promoter of DNA methyltransferase 3 beta (DNMT3B), leading to the transcriptional inhibition of DNMT3B. This subsequently results in a reduced methylation of CYGB promoter, ultimately inhibiting the tumor progression of BCa. SOX7 + CYGB scores were significantly linked to patient prognosis. In conclusion, SOX7 inhibits the malignant progression of BCa via the DNMT3B/CYGB axis. Additionally, the SOX7 + CYGB score is capable of predicting the prognostic outcomes of BCa patients. Therefore, SOX7 and CYGB may play an important role in the progression of bladder cancer, and they can be used as prognostic markers of bladder cancer patients.

Prognostic impact of DTA mutation and co-occurring mutations in patients with myelodysplastic syndrome.

OBJECTIVE: To evaluate the frequency and prognostic significance of DTA (DNMT3A、TET2、ASXL1) gene mutation and co-occurring mutations in patients with myelodysplastic syndrome (MDS). METHODS: The clinical data of 102 newly diagnosed MDS patients who accepted Next Generation Sequencing (NGS) was retrospectively analyzed. According to whether the patients had DTA gene mutation, the patients were divided into DTA mutated (DTA-mut) group and wild type (DTA-wt) group, and the relationship between gene mutation and clinical characteristics and prognosis was analyzed. RESULTS: Among the 102 MDS patients, 96% (98/102) presented with mutation, while the mean number of mutations was 3.04 mutations/patient. DTA-mut was detected in 56.9% (58/102) patients. The most frequent co-mutated genes in DTA-mut group were SF3B1 (25.8%), RUNX1 (24.1%), U2AF1 (18.9%), SRSF2, EZH2, SETBP1 (17.2%), STAG2 (15.5%), IDH2 (12.1%) and BCOR, CBL (10.3%). The two groups showed no significant differences in ages, blood parameters, bone marrow blasts, WHO 2022 classification, IPSS-R risk category and rate of conversion to leukemia. Compared with the DTA-wt group, the mutation frequency of RUNX1 was higher (P = 0.02), while mutation frequency of TP53 was lower (P = 0.001) and the mutation frequency of ≥ 3 co-mutated genes was higher in DTA-mut group (P = 0.00). Survival analysis showed that the overall survivals (OS) of DTA-mut patients was significantly inferior to that of DTA-wt patients (P = 0.0332). According to IPSS-R classification, a statistically significant difference in OS was only observed in higher risk (IPSS-R > 3.5) group (P = 0.0058). In the context of DTA mutation, the OS of patients with RUNX1 mutation was shorter than that of patients without RUNX1 mutation significantly (P = 0.0074). The OS of patients with SF3B1 mutation was longer than that of patients without SF3B1 mutation, but there was no statistical difference (P = 0.0827). DTA mutations were not independent prognostic factors when DTA and co-mutated genes with frequency > 10% were considered in Cox regression model (P = 0.329). However, multivariate analysis confirmed an independently adverse prognosis of RUNX1 co-mutation (P = 0.042, HR = 2.426, 95% CI:1.031-5.711) in DTA-mut cohort. Moreover, our multivariable analysis suggests that SRSF2-mut was an independent poor prognostic factor for all MDS patients (P = 0.047), but lost significance (P = 0.103) for DTA-mut patients. CONCLUSIONS: DTA mutations are frequently observed in patients with MDS, often accompanied by genes involved in RNA splicing and transcription factors like SF3B1 and RUNX1. DTA and concomitant mutations affect prognosis in MDS patients and RUNX1 was identified as an independent poor prognostic factor in patients with DTA mutations.

Effective Treatment with Venetoclax and Hypomethylating Agents for the Coexistence of Multiple Myeloma and Acute Myeloid Leukemia: A Case Report and Literature Review.

OBJECTIVE: Multiple myeloma (MM) and Acute myeloid leukemia (AML) are distinct hematologic malignancies originating from different cell lineages. Their coexistence is extremely rare, and current treatment approaches are even more so. Therefore, exploring the clinical features of their coexistence and the promising treatment strategy is worthwhile. CASE REPORT: We described three cases involving the coexistence of MM and DNMT3A-mutant AML, two of which presented simultaneous occurrences, while Case 3 had secondary AML about 70 months after the MM. DISCUSSION: All cases exhibited DNMT3A mutations, which characterized by one missense mutation and two frameshift mutations; all were likely loss of function mutations. Among them, two patients were treated with Venetoclax-based regimens and achieved favorable effects. The patients were alive for 62,38 and 103 months. CONCLUSIONS: Clonal hematopoiesis of DNMT3A may have a crucial role in the coexistence of MM and AML and Venetoclax-based regimens reveal favorable treatment responses. However, drug resistance still needs to be considered, and further research is required to elucidate the underlying mechanisms and treatment strategies.

An engineered cellular carrier delivers miR-138-5p to enhance mitophagy and protect hypoxic-injured neurons via the DNMT3A/Rhebl1 axis.

Mitophagy influences the progression and prognosis of ischemic stroke (IS). However, whether DNA methylation in the brain is associated with altered mitophagy in hypoxia-injured neurons remains unclear. Here, miR-138-5p was found to be highly expressed in exosomes secreted by astrocytes stimulated with oxygen and glucose deprivation/re-oxygenation (OGD/R), which could influence the recovery of OGD/R-injured neurons through autophagy. Mechanistically, miR-138-5p promotes the stable expression of Ras homolog enriched in brain like 1(Rhebl1) through DNA-methyltransferase-3a (DNMT3A), thereby enhancing ubiquitin-dependent mitophagy to maintain mitochondrial homeostasis. Furthermore, we employed glycosylation engineering and bioorthogonal click reactions to load mirna onto the surface of microglia and deliver them to injured region utilising the inflammatory chemotactic properties of microglia to achieve drug-targeted delivery to the central nervous system (CNS). Our findings demonstrate miR-138-5p improves mitochondrial function in neurons through the miR-138-5p/DNMT3A/Rhebl1 axis. Additionally, our engineered cell vector-targeted delivery system could be promising for treating IS. STATEMENT OF SIGNIFICANCE: In this study, we demonstrated that miR-138-5p in exosomes secreted by astrocytes under hypoxia plays a critical role in the treatment of hypoxia-injured neurons. And we find a new target of miR-138-5p, DNMT3A, which affects neuronal mitophagy and thus exerts a protective effect by regulating the methylation of Rbebl1. Furthermore, we have developed a carrier delivery system by combining miR-138-5p with the cell membrane of microglia and utilized the inflammatory chemotactic properties of microglia to deliver this system to the brain via intravenous injection. This groundbreaking study not only provides a novel therapeutic approach for ischemia-reperfusion treatment but also establishes a solid theoretical foundation for further research on targeted drug delivery for central nervous system diseases with promising clinical applications.

[Aging and clonal hematopoesis.]

The number of somatic mutations among all tissues increases along with age. This process was well-studied in hematopoietic stem cells (HSCs). Some mutations lead to a proliferative advantage and expansion of HSCs to form a dominant clone. Clonal hematopoiesis is general in the elderly population. Clonal hematopoiesis of indeterminate potential (CHIP) is a more common phenomenon in the elderly and is defined as somatic mutations in clonal blood cells without any other hematological malignancies. The development of CHIP is an independent risk factor for hematological malignancies, cardiovascular diseases, and reduced overall survival. CHIP is frequently associated with mutations in DNMT3A and TET2 genes involved in DNA methylation. The epigenetic human body clocks have been developed based on the age-related changes in methylation, making it possible to detect epigenetic aging. The combination of epigenetic aging and CHUP is associated with adverse health outcomes. Further research will reveal the significance of clonal hematopoiesis and CHIP in aging, acquiring various diseases, and determining the feasibility of influencing the mutagenic potential of clones.

[Research progress on DNMT3A gene expression in Acute myeloid leukemia].

DNA methylation is an important epigenetic regulatory mechanism which plays a crucial role in cell differentiation and development. Its function is closely related to DNA methyltransferase 3 alpha (DNMT3A), which can affect gene expression and stem cell differentiation. The mutation rate of the DNMT3A gene is relatively high in Acute myeloid leukemia (AML), but its type and pathogenic mechanism are not yet clear. Further research on DNMT3A may help to identify its pathogenic targets and provide a basis for precise treatment of AML. This article has provided a review for the research progress on the expression of the DNMT3A gene in AML.

Saliva-derived DNA is suitable for the detection of clonal haematopoiesis of indeterminate potential.

Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with many adverse health outcomes. However, further research is required to understand the critical genes and pathways relevant to CHIP subtypes, evaluate how CHIP clones evolve with time, and further advance functional characterisation and therapeutic studies. Large epidemiological studies are well placed to address these questions but often collect saliva rather than blood from participants. Paired saliva- and blood-derived DNA samples from 94 study participants were sequenced using a targeted CHIP-gene panel. The ten genes most frequently identified to carry CHIP-associated variants were analysed. Fourteen unique variants associated with CHIP, ten in DNMT3A, two in TP53 and two in TET2, were identified with a variant allele fraction (VAF) between 0.02 and 0.2 and variant depth ≥ 5 reads. Eleven of these CHIP-associated variants were detected in both the blood- and saliva-derived DNA sample. Three variants were detected in blood with a VAF > 0.02 but fell below this threshold in the paired saliva sample (VAF 0.008-0.013). Saliva-derived DNA is suitable for detecting CHIP-associated variants. Saliva can offer a cost-effective biospecimen that could both advance CHIP research and facilitate clinical translation into settings such as risk prediction, precision prevention, and treatment monitoring.

[Prognostic Value of DTA Mutations in Patients with Newly Diagnosed Acute Myeloid Leukemia].

OBJECTIVE: To investigate the prognostic significance of DTA (DNMT3A, TET2, ASXL1 ) gene mutations in patients with non-M3 acute myeloid leukemia (AML). METHODS: The clinical data of 180 newly diagnosed AML patients hospitalized in the First People's Hospital of Changzhou from January 2018 to April 2022 were retrospectively analyzed. Next-generation sequencing technology was used to detect 150 gene mutations in the patients, and log-rank tests and Cox regression models were used to analyze the prognostic factors. RESULTS: DTA gene mutations were detected in 83 (46.1%) of 180 AML patients. Compared to patients without DTA mutations, patients with DTA mutations were significantly older (P < 0.001). The median overall survival (OS) time and disease-free survival (DFS) time in the DTA mutation group were significantly shorter than those in the group without DTA mutation (both P < 0.05). Multivariate analysis showed that age ≥ 60 years (P < 0.001), with DTA mutation (P =0.018), and intermediate-risk (relative to favorable-risk) (P =0.005) were independent risk factors for OS in AML patients. CONCLUSION: AML patients with DTA mutations are relatively older, with shorter median OS time and DFS time, and poor prognosis.

Paternal high-fat diet affects weight and DNA methylation of their offspring.

Obesity poses a public health threat, reaching epidemic proportions. Our hypothesis suggests that some of this epidemic stems from its transmission across generations via paternal epigenetic mechanisms. To investigate this possibility, we focused on examining the paternal transmission of CpG methylation. First-generation male Wistar rats were fed either a high-fat diet (HF) or chow and were mated with females fed chow. We collected sperm from these males. The resulting offspring were raised on a chow diet until day 35, after which they underwent a dietary challenge. Diet-induced obese (DIO) male rats passed on the obesogenic trait to both male and female offspring. We observed significant hypermethylation of the Pomc promoter in the sperm of HF-treated males and in the hypothalamic arcuate nucleus (Arc) of their offspring at weaning. However, these differences in Arc methylation decreased later in life. This hypermethylation is correlated with increased expression of DNMT3B. Further investigating genes in the Arc that might be involved in obesogenic transgenerational transmission, using reduced representation bisulfite sequencing (RRBS) we identified 77 differentially methylated regions (DMRs), highlighting pathways associated with neuronal development. These findings support paternal CpG methylation as a mechanism for transmitting obesogenic traits across generations.

Clonal Hematopoiesis Is Associated With Long-Term Adverse Outcomes Following Cardiac Surgery.

BACKGROUND: Cardiac surgery triggers sterile innate immune responses leading to postoperative complications. Clonal hematopoiesis (CH) is associated with short-term inflammation-mediated outcomes after cardiac surgery. The impact of CH on long-term postoperative outcomes remains unknown. METHODS AND RESULTS: In this cohort study, patients undergoing elective cardiac surgery were included from January 2017 to September 2019. Patients were screened for CH using a predefined gene panel of 19 genes. Recorded clinical events were all-cause death, major adverse cardiac and cerebral events including cardiovascular death, myocardial infarction or nonscheduled coronary revascularization, stroke, and hospitalization for acute heart failure. The primary study outcome was time to a composite criterion including all-cause mortality and major adverse cardiac and cerebral events. Among 314 genotyped patients (median age: 67 years; interquartile range 59-74 years), 139 (44%) presented with CH, based on a variant allelic frequency ≥1%. Carriers of CH had a higher proportion of patients with a history of atrial fibrillation (26% for CH versus 17% for non-CH carriers, P=0.022). The most frequently mutated genes were DNMT3A, TET2, and ASXL1. After a median follow-up of 1203 [813-1435] days, the primary outcome occurred in 50 patients. After multivariable adjustment, CH was independently associated with a higher risk for the primary outcome (hazard ratio, 1.88 [95% CI, 1.05-3.41], P=0.035). Most adverse events occurred in patients carrying TET2 variants. CONCLUSIONS: In patients undergoing cardiac surgery, CH is frequent and associated with a 2-fold increased long-term risk for major adverse clinical outcomes. CH is a novel risk factor for long-term postcardiac surgery complications and might be useful to personalize management decisions. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03376165.

Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.

During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 amino terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Further, aberrant redistribution of DNMT3A1 to Polycomb target genes recapitulates the cancer-associated DNA hypermethylation signature and inhibits their transcriptional activation during cell differentiation. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for mediating promoter CpG island DNA hypermethylation, a major molecular hallmark of cancer.

6-Gingerol modulates miRNAs and PODXL gene expression via methyltransferase enzymes in NB4 cells: an in silico and in vitro study.

This investigation delves into the influence of predicted microRNAs on DNA methyltransferases (DNMTs) and the PODXL gene within the NB4 cell line, aiming to elucidate their roles in the pathogenesis of acute myeloid leukemia (AML). A comprehensive methodological framework was adopted to explore the therapeutic implications of 6-gingerol on DNMTs. This encompassed a suite of bioinformatics tools for protein structure prediction, docking, molecular dynamics, and ADMET profiling, alongside empirical assessments of miRNA and PODXL expression levels. Such a multifaceted strategy facilitated an in-depth understanding of 6-gingerol's potential efficacy in DNMT modulation. The findings indicate a nuanced interplay where 6-gingerol administration modulated miRNA expression levels, decreasing in DNMT1 and DNMT3A expression in NB4 cells. This alteration indirectly influenced PODXL expression, contributing to the manifestation of oncogenic phenotypes. The overexpression of DNMT1 and DNMT3A in NB4 cells may contribute to AML, which appears modulable via microRNAs such as miR-193a and miR-200c. Post-treatment with 6-gingerol, DNMT1 and DNMT3A expression alterations were observed, culminating in the upregulation of miR-193a and miR-200c. This cascade effect led to the dysregulation of tumor suppressor genes in cancer cells, including downregulation of PODXL, and the emergence of cancerous traits. These insights underscore the therapeutic promise of 6-gingerol in targeting DNMTs and microRNAs within the AML context.

Epigenetic markers of tooth eruption - DNA methylation and histone acetylation.

The present study aimed to evaluate whether epigenetic markers are expressed in the dental follicles surrounding ectopically erupting teeth. Twenty-one dental follicles were collected in 20 adolescent children through surgical exposure of ectopic teeth. The epigenetic modifications of DNA methylation and histone acetylation were evaluated by immunohistochemistry. The results showed cells positive for DNA-methyltransferase 1 (DNMT1), DNA methyltransferase 3 beta (DNMT3B), ten-eleven translocation-2 (TET2), acetyl-histone H3 (AcH3), acetyl-histone H4 (AcH4), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC) were present in all the samples. The levels of epigenetic markers representing active chromatin (5hmC, AcH3, AcH4, and TET2) were statistically significantly higher than those of markers representing inactive chromatin (5mC, DNMT3B, DNMT1). In conclusion, follicles in ectopic teeth display major epigenetic modifications. In the follicles, epigenetic markers associated with the activation of bone-related genes are more abundant than markers associated with the inactivation of bone-related genes.

Mecp2 promotes the anti-inflammatory effect of alpinetin via epigenetic modification crosstalk.

In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti-inflammatory agents, alpinetin has shown promising anti-inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti-inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF-KB family) and p300 (a type of co-activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti-inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti-inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2's anti-inflammatory assistance. In conclusion, Mecp2 may augment the anti-inflammatory effects of alpinetin through epigenetic 'crosstalk', highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti-inflammatory intervention.

DNA methylation of miR-181a-5p mediated by DNMT3b drives renal interstitial fibrosis developed from acute kidney injury.

Aim: To explore the role of miR-181a-5p in the progression of acute kidney injury (AKI) to renal interstitial fibrosis (RIF) from the perspective of DNA methylation.Materials & methods: The role of miR-181a-5p was confirmed by collecting clinical samples, injecting miR-181a-5p agomir into tail vein, and transfecting miR-181a-5p mimic in vitro. The mechanism of miR-181a-5p's influence on AKI induced RIF was investigated by methylation-specific PCR, bioinformatic analysis, transcriptome sequencing and so on.Results: MiR-181a-5p plays an important role in AKI induced RIF. DNMT3b-mediated miR-181a-5p promoter hypermethylation is the main reason for the downregulation of miR-181a-5p. HDAC9 and SNAI2 are direct targets of miR-181a-5p.Conclusion: Hypermethylation of miR-181a-5p promoter mediated by DNMT3b promotes AKI induced RIF by targeting HDAC9 and SNAI2.

[Box: see text].