Abnormal DNA Methylation Research Articles

Identification of CAPG as a potential prognostic biomarker associated with immune cell infiltration and ferroptosis in uterine corpus endometrial carcinoma.

Capping actin protein, gelsolin-like (CAPG) is a potential therapeutic target in various cancers. However, the potential immunotherapeutic effects and prognostic value of CAPG in uterine corpus endometrial carcinoma (UCEC) remain unclear. The characterization, methylation effects, prognostic value, targeted miRNAs of CAPG, and the correlation of CAPG with immune cell infiltration and ferroptosis in UCEC were investigated using multiple public databases and online tools. Furtherly, we explored the potential physiological function of CAPG using EdU and Transwell migration assays, identified the cell localization and expression of CAPG and GPX4 by immunofluorescence, and detected the intracellular Fe2+ levels using a FerroOrange fluorescent probe in Ishikawa cells. Additionally, the OncoPredict package was used to analyze the potential chemotherapeutic drugs for UCEC. CAPG showed generally high expression in tumor group. The overall survival rate of the high-risk group was significantly lower than that of the low-risk group. Enrichment analysis indicated that CAPG is involved in immune-related pathways and is closely associated with the tumor microenvironment. CAPG expression levels were affected by abnormal DNA methylation and/or targeted miRNAs, infiltration levels and marker genes of various immune cells, thereby impacting immune response, ferroptosis, and patient prognosis. Ferroptosis analysis indicated that ALOX5 and VLDLR were the top CAPG-related ferroptosis markers; glutathione metabolism levels in tumor group were generally high, and decitabine was a ferroptosis inducer. CAPG-siRNA suppressed the cell proliferation and invasion, and markedly elevated the expression levels of immune-related genes IL8, TNF, TLR4 and the intracellular Fe2+ levels. CAPG co-located with GPX4 in nucleus and co-regulated ferroptosis and metabolism in Ishikawa cells. Moreover, four chemotherapy drugs showed better sensitivity to UCEC patients in the low-risk cohort. CAPG may serve as a potential biomarker of UCEC owing to its role in modulating the immune response and ferroptosis, providing novel perspectives for combined immunotherapy of UCEC.

Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein.

DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1-targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis-targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50=643/899 nM in MV4-11/MOLM-13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1-selective degradation in a dose- and time-dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor-suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1-targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1-related studies.

Genome-wide integrated DNA methylome and transcriptome analysis reveals a strong dysregulated myeloid component in the epigenetic landscape of Systemic Sclerosis.

Non-genetic factors influence Systemic Sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study (EWAS). We analyzed DNA methylation data from whole blood samples in 179 SSc patients and 241 unaffected individuals, to identify differentially methylated positions (DMPs) with a FDR<0.05. These results were further integrated with RNA-seq data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels. This analysis yielded 525 DMPs enriched in immune-related pathways, being leukocyte cell-cell adhesion the most significant (FDR=4.91x10-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach we observed an enrichment of neutrophil related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein (CEBP) transcription factor family in SSc, which is crucial in the myeloid lineage development. Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.

DNA methylation-driven gene FAM3D promotes colorectal cancer growth via the ATF4-SESN2-mTORC1 pathway.

Globally, colorectal cancer (CRC) is the malignant tumor with the highest mortality rate after lung cancer. Abnormal DNA methylation drives dysregulated gene expression, thereby promoting CRC progression and leading to poor prognosis. We identified a 3-CpG methylation signature that is independently associated with CRC prognosis. The model consists of three methylation-driven genes: FAM3 Metabolism Regulating Signaling Molecule D (FAM3D), DAPP1, and PIGR. However, the prognostic significance, biological function, and related mechanisms of the individual methylation-driven gene FAM3D in CRC have not been studied. Here, we discovered that FAM3D expression was reduced in CRC tissues and cells, and that high methylation and low expression of FAM3D were independent prognostic risk factors for CRC. In addition, FAM3D promoted the growth and movement of CRC cells in vitro and the proliferation in nude mice, mainly by inhibiting ATF4 transcription and downregulating SESN2 expression, and ultimately activating mTORC1. Furthermore, FAM3D resulted in reduced sensitivity of CRC cells to oxaliplatin, cisplatin, and 5-fluorouracil. Our study showed that FAM3D activates the mTORC1 pathway through the ATF4-SESN2 axis and promotes the malignant progression of CRC, which contributes to predict CRC prognosis and guide individualized treatment.

Impact of Physical Activity on DNA Methylation Signatures in Breast Cancer Patients: A Systematic Review with Bioinformatic Analysis.

Breast cancer (BC) continues to significantly impact women worldwide. Numerous studies show that physical activity (PA) significantly enhances the quality of life, aids recovery, and improves survival rates in BC patients. PA's influence extends to altering DNA methylation patterns on both a global and gene-specific scale, potentially reverting abnormal DNA methylation, associated with carcinogenesis and various pathologies. This review consolidates the findings of the current literature, highlighting PA's impact on DNA methylation in BC patients. Our systematic analysis indicates that PA may elevate global DNA methylation within tumour tissues. Furthermore, it appears to modify gene-specific promoter methylation across a wide spectrum of genes in various tissues. Through bioinformatic analysis, to investigate the functional enrichment of these affected genes, we identified a predominant enrichment in metabolic pathways, cell cycle regulation, cell cycle checkpoints, mitosis, cellular stress responses, and molecular functions governing diverse binding processes. The Human Protein Atlas corroborates this enrichment, indicating gene functionality across 266 tissues, notably within various breast tissues. This systematic review unveils PA's capacity to systematically alter DNA methylation patterns across multiple tissues, particularly in BC patients. Emphasising its influence on crucial biological processes and functions, this alteration holds potential for restoring normal cellular functionality and the cell cycle. This reversal of cancer-associated patterns could potentially enhance recovery and improve survival outcomes.

The Epigenetic Contribution to the Pathogenesis of Psoriasis: Recent Advances.

Psoriasis is defined as a chronic autoimmune disorder of the skin in which abnormal proliferation and differentiation of keratinocytes are blamed as the central culprit of disease etiopathogenesis. A complex interplay between environmental factors and genetic risk factors has been suggested to trigger the disease. However, epigenetic regulation appears to connect external stimuli and genetic abnormalities in the development of psoriasis. The discordance in the prevalence of psoriasis between monozygotic twins and environmental factors that contribute to its onset have caused a paradigm shift regarding the mechanisms underlying the pathogenesis of this disease. Epigenetic dysregulation may be involved in aberrancies of keratinocyte differentiation, T-cell activation, and other plausible cells, leading to the initiation and perpetuation of psoriasis. Epigenetics is characterized by heritable alterations in the transcription of genes without nucleotide change and is commonly considered at three levels, i.e., DNA methylation, histone modifications, and microRNAs. To date, scientific evidence has indicated abnormal DNA methylation, histone modifications, and non-coding RNA transcription in psoriatic patients. In order to reverse aberrant epigenetic changes in psoriasis patients, several compounds and drugs (epi-drugs) have been developed to affect the major enzymes involved in the methylation of DNA, or the acetylation of histones, which aim to correct the aberrant methylation and acetylation patterns. A number of clinical trials have suggested the therapeutic potential of such drugs in the treatment of psoriasis. In the present review, we attempt to clarify recent findings with respect to epigenetic irregularities in psoriasis and discuss future challenges.

DNA Methylation in Autism Spectrum Disorders: Biomarker or Pharmacological Target?

Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental disabilities with persistent impairments in cognition, communication, and social behavior. Although environmental factors play a role in ASD etiopathogenesis, a growing body of evidence indicates that ASD is highly inherited. In the last two decades, the dramatic rise in the prevalence of ASD has interested researchers to explore the etiologic role of epigenetic marking and incredibly abnormal DNA methylation. This review aimed to explain the current understanding of the association between changes in DNA methylation signatures and ASD in patients or animal models. We reviewed studies reporting alterations in DNA methylation at specific genes as well as epigenome-wide association studies (EWASs). Finally, we hypothesized that specific changes in DNA methylation patterns could be considered a potential biomarker for ASD diagnosis and prognosis and even a target for pharmacological intervention.

Loss of Tet hydroxymethylase activity causes mouse embryonic stem cell differentiation bias and developmental defects.

The TET family is well known for active DNA demethylation and plays important roles in regulating transcription, the epigenome and development. Nevertheless, previous studies using knockdown (KD) or knockout (KO) models to investigate the function of TET have faced challenges in distinguishing its enzymatic and nonenzymatic roles, as well as compensatory effects among TET family members, which has made the understanding of the enzymatic role of TET not accurate enough. To solve this problem, we successfully generated mice catalytically inactive for specific Tet members (Tetm/m). We observed that, compared with the reported KO mice, mutant mice exhibited distinct developmental defects, including growth retardation, sex imbalance, infertility, and perinatal lethality. Notably, Tetm/m mouse embryonic stem cells (mESCs) were successfully established but entered an impaired developmental program, demonstrating extended pluripotency and defects in ectodermal differentiation caused by abnormal DNA methylation. Intriguingly, Tet3, traditionally considered less critical for mESCs due to its lower expression level, had a significant impact on the global hydroxymethylation, gene expression, and differentiation potential of mESCs. Notably, there were common regulatory regions between Tet1 and Tet3 in pluripotency regulation. In summary, our study provides a more accurate reference for the functional mechanism of Tet hydroxymethylase activity in mouse development and ESC pluripotency regulation.

FLI1 is associated with regulation of DNA methylation and megakaryocytic differentiation in FPDMM caused by a RUNX1 transactivation domain mutation

Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1. It is characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematological malignancies. Although FPDMM is a precursor for diseases involving abnormal DNA methylation, the DNA methylation status in FPDMM remains unknown, largely due to a lack of animal models and challenges in obtaining patient-derived samples. Here, using genome editing techniques, we established two lines of human induced pluripotent stem cells (iPSCs) with different FPDMM-mimicking heterozygous RUNX1 mutations. These iPSCs showed defective differentiation of hematopoietic progenitor cells (HPCs) and megakaryocytes (Mks), consistent with FPDMM. The FPDMM-mimicking HPCs showed DNA methylation patterns distinct from those of wild-type HPCs, with hypermethylated regions showing the enrichment of ETS transcription factor (TF) motifs. We found that the expression of FLI1, an ETS family member, was significantly downregulated in FPDMM-mimicking HPCs with a RUNX1 transactivation domain (TAD) mutation. We demonstrated that FLI1 promoted binding-site-directed DNA demethylation, and that overexpression of FLI1 restored their megakaryocytic differentiation efficiency and hypermethylation status. These findings suggest that FLI1 plays a crucial role in regulating DNA methylation and correcting defective megakaryocytic differentiation in FPDMM-mimicking HPCs with a RUNX1 TAD mutation.

Pregnancy induced hypertension and umbilical cord blood DNA methylation in newborns: an epigenome-wide DNA methylation study

ObjectiviesPregnancy induced hypertension (PIH) syndrome is a disease that unique to pregnant women and is associated with elevated risk of offspring cardiovascular diseases (CVDs) and neurodevelopmental disorders in their kids. Previous research on cord blood utilizing the Human Methylation BeadChip or EPIC array revealed that PIH is associated with specific DNA methylation site. Here, we investigate the whole genome DNA methylation landscape of cord blood from newborns of PIH mother.MethodsWhole-genome bisulfite sequencing (WGBS) was used to examine the changes in whole genome DNA methylation in the umbilical cord blood of three healthy (NC) and four PIH individuals. Using methylKit, we discovered Hypo- and hyper- differentially methylated probes (DMPs) or methylated regions (DMRs) in the PIH patients’ cord blood DNA. Pathway enrichments were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays. DMPs or DMRs relevant to the immunological, neurological, and circulatory systems were also employed for enrichment assay, Metascape analysis and PPI network analysis.Results520 hyper- and 224 hypo-DMPs, and 374 hyper- and 186 hypo-DMRs between NC and PIH group, respectively. Both DMPs and DMRs have enhanced pathways for cardiovascular, neurological system, and immune system development. Further investigation of DMPs or DMRs related to immunological, neurological, and circulatory system development revealed that TBK1 served as a hub gene for all three developmental pathways.ConclusionPIH-associated DMPs or DMRs in umbilical cord blood DNA may play a role in immunological, neurological, and circulatory system development. Abnormal DNA methylation in the immune system may also contribute to the development of CVDs and neurodevelopment disorders.

Chromatin modifiers in endometriosis pathogenesis

Introduction. It was revealed that various epigenetic abnormalities may play an important role in the endometriosis pathogenesis. The regulation of chromatin structure is carried out mainly by chromatin modifiers (CMs), which stimulate generation of genomic regions with different functional structures and thus change the patterns or levels of gene expression by exerting expected biological functions and causing epigenetic changes.Aim: to consider СМs role in endometriosis pathogenesis and their regulation mechanism assessing current publications.Materials and Methods. The search was conducted in the databases PubMed, Scopus, Web of Science, Google Scholar and eLibrary. Keywords and phrases in Russian and English related to the research topic were used as follows: "endometriosis", "chromatin modifiers", "histone acetylation", "DNA methylation", "microRNA", "endometriosis", "chromatin modifiers", "histone acetylation", "DNA methylation", "microRNA". The evaluation of articles was carried out in accordance with PRISMA recommendations.Results. Chromatin modifiers control differentiation, growth and development, aging and cell death by interacting with various functional chromatin elements. They can cause abnormal gene expression by regulating chromatin structure affecting emergence and development of endometriosis. DNA methylation determines cell types, controls gene expression and genome stability. Abnormal DNA methylation in gene promoter regions necessary for normal endometrial response affects endometriosis development. DNA methyltransferase (DNMT) inhibitors reduce the methylation of human homeobox A10 (HOXA10) and progesterone receptor (PR) genes and potentiate their expression in endometrial cells, improving endometrial susceptibility and inhibiting cell cycle progression. Abnormal histone modifications in endometrial cells may facilitate or hinder the access of transcription mechanisms to chromatin DNA. Histone deacetylase inhibitors effectively eliminate the effects of abnormal histone modifications in endometriosis cells and prevent endometriosis progression. The expression of non-coding RNAs and chromatin remodeling complexes also alters chromatin structure being involved in arising endometriosis and is associated with infertility by promoting proliferation, invasion and migration of endometriod cells.Conclusion. Chromatin modifiers play a key role in developing endometriosis by controlling gene expression and chromatin structure. Understanding underlying mechanisms provides valuable information for diagnostics and development of new approaches to treat endometriosis.

DNA methylation modification in Idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial lung disease with a prognosis worse than lung cancer. It is a fatal lung disease with largely unknown etiology and pathogenesis, and no effective therapeutic drugs render its treatment largely unsuccessful. With continuous in-depth research efforts, the epigenetic mechanisms in IPF pathogenesis have been further discovered and concerned. As a widely studied mechanism of epigenetic modification, DNA methylation is primarily facilitated by DNA methyltransferases (DNMTs), resulting in the addition of a methyl group to the fifth carbon position of the cytosine base, leading to the formation of 5-methylcytosine (5-mC). Dysregulation of DNA methylation is intricately associated with the advancement of respiratory disorders. Recently, the role of DNA methylation in IPF pathogenesis has also received considerable attention. DNA methylation patterns include methylation modification and demethylation modification and regulate a range of essential biological functions through gene expression regulation. The Ten-Eleven-Translocation (TET) family of DNA dioxygenases is crucial in facilitating active DNA demethylation through the enzymatic conversion of the modified genomic base 5-mC to 5-hydroxymethylcytosine (5-hmC). TET2, a member of TET proteins, is involved in lung inflammation, and its protein expression is downregulated in the lungs and alveolar epithelial type II cells of IPF patients. This review summarizes the current knowledge of pathologic features and DNA methylation mechanisms of pulmonary fibrosis, focusing on the critical roles of abnormal DNA methylation patterns, DNMTs, and TET proteins in impacting IPF pathogenesis. Researching DNA methylation will enchance comprehension of the fundamental mechanisms involved in IPF pathology and provide novel diagnostic biomarkers and therapeutic targets for pulmonary fibrosis based on the studies involving epigenetic mechanisms.

Novel Transcriptional and DNA Methylation Abnormalities of SORT1 Gene in Non-Small Cell Lung Cancer.

Sortilin is an important regulator with potential tumour-suppressor function by limiting EGFR signalling. In this study, we undertook a comprehensive expression analysis of sortilin transcript variants and the DNA methylation status of their corresponding promoters in human non-small cell carcinomas (NSCLCs). RNA/DNA was extracted from 81 NSCLC samples and paired normal tissue. mRNA expression was measured by qPCR and DNA methylation determined by pyrosequencing. BigDye-terminator sequencing was used to confirm exon-8 alternative splicing. Results demonstrated that both SORT1A and SORT1B variants were downregulated in lung tumours. The SORT1A/SORT1B expression ratio was higher in tumours compared to normal tissue. SORT1B promoter hypermethylation was detected in lung tumours compared to normal lung (median difference 14%, Mann-Whitney test p = 10-6). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%, p = 10-15) was observed in the lung cancer cases compared to control subjects. We demonstrate that the SORT1B exon-8 splice variation, reported in sequence databases, is also a feature of SORT1A. The significantly altered quantitative and qualitative characteristics of sortilin mRNA in NSCLC indicate a significant involvement in tumour pathogenesis and may have significant impact for its utility as a predictive marker in lung cancer management.

Clinical, epidemiological and genetic features of colorectal cancer

Introduction. The incidence of colorectal cancer for 2020 was 1931590 cases, which is 10 % of all new cases of incidence, and mortality from colorectal cancer ranks 2nd among cancer deaths, it is 935 173 cases (9.4 %) according to Globocan 2020. According to statistics of the Kazakh Research Institute of Oncology and Radiology for 2019–2020 сolorectal cancer ranks 3rd in the structure of oncopathology, both in terms of morbidity and mortality. The occurrence of colorectal cancer is associated with an interaction that occurs at several levels between hereditary, environmental and individual factors. Understanding the molecular basis is important because it can identify factors that initiate development, maintain progression, and determine response or resistance to anticancer agents.Aim. To describe the main genetic mutations and their impact on treatment prognosis, diagnosis and course of colorectal cancer.Materials and methods. A systematic literature review of scientific databases Cochrane, PubMEd, MedLine, Elsevier was carried out. For the main search, the main search terms are formulated: colorectal cancer, mutations in colorectal cancer, molecular genetic studies in colorectal cancer, mutation of the KRAS gene. Also, a time range was set no later than 5 years, i. e. all articles published from 2017 to the current year.Results. The main molecular changes in colorectal cancer are Chromosome instability, microsatellite instability, and abnormal DNA methylation. Suppressor genes, such as Ras, EGFR (Erb-B1), Erb-B2, TGF-alpha, and TGF-beta 1, are also of great importance.Conclusion. Research that contributes to the understanding of the molecular basis of colorectal cancer helps in the early diagnosis of familial cancer, treatment prognosis and a personalized approach to patient treatment.

Pan-cancer analysis reveals correlation between RAB3B expression and tumor heterogeneity, immune microenvironment, and prognosis in multiple cancers

RAB3B is essential for the transportation and secretion within cells. Its increased expression is linked to the development and progression of various malignancies. However, understanding of RAB3B’s involvement in carcinogenesis is mostly limited to specific cancer subtypes. Hence, exploring RAB3B's regulatory roles and molecular mechanisms through comprehensive cancer datasets might offer innovative approaches for managing clinical cancer. To examine the potential involvement of RAB3B in the development of cancer, we analyzed data from various sources including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), cBioPortal, HPA, UALCAN, and tissue microarray (TAM). Using bioinformatics techniques, we examined the correlation between RAB3B expression and prognosis, tumor heterogeneity, methylation modifications, and immune microenvironment across different cancer types. Our findings indicate that elevated RAB3B expression can independently predict prognosis in many tumors and has moderate accuracy for diagnosing most cancers. In most cancer types, we identified RAB3B mutations that showed a significant correlation with tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), and microsatellite instability (MSI). Abnormal DNA methylation patterns were also observed in most cancers compared to normal tissues. Additionally, we found significant correlations between RAB3B expression, immune cell infiltration, and immune scores across various cancers. Through pan-cancer analysis, we observed significant differences in RAB3B expression levels between tumors and normal tissues, making it a potential primary factor for cancer diagnosis and prognosis. The IHC results revealed that the expression of RAB3B in six types of tumors was consistent with the results of the pan-cancer analysis of the database. Furthermore, RAB3B showed potential associations with tumor heterogeneity and immunity. Thus, RAB3B can be utilized as an auxiliary diagnostic marker for early tumor detection and a prognostic biomarker for various tumor types.

Mechanisms of Heavy Metal Cadmium (Cd)-Induced Malignancy.

The environmental pollution of cadmium is worsening, and its significant carcinogenic effects on humans have been confirmed. Cadmium can induce cancer through various signaling pathways, including the ERK/JNK/p38MAPK, PI3K/AKT/mTOR, NF-κB, and Wnt. It can also cause cancer by directly damaging DNA and inhibiting DNA repair systems, or through epigenetic mechanisms such as abnormal DNA methylation, LncRNA, and microRNA. However, the detailed mechanisms of Cd-induced cancer are still not fully understood and require further investigation.

Decreased vitamin D bio-availability with altered DNA methylation of its metabolism genes in association with the metabolic disorders among the school-aged children with degree I, II, and III obesity

Obesity is strongly associated with disturbances of vitamin D (VD) metabolites in the animal models. However, the related epidemiological evidence is still controversial, especially the different degrees of obesity children. Hence, in this present representative case-control study, 106 obesity school-age children aged 7–12 years were included and divided into different subgroups as degree I (the age- and sex-specific BMI≥95th percentile, n=45), II (BMI ≥120% percentile, n=34) and III (BMI ≥140% percentile, n=27) obesity groups across the ranges of body mass index (BMI). While the age- and sex-matched subjects without obesity were as the control group. Notably, it was significantly different of body composition, anthropological and clinical characteristics among the above four subgroups with the dose-response relationships (P<.05). Moreover, comparing with the control group, the serum VD concentrations were higher, VD metabolites like 25(OH)D, 25(OH)D3 and 1,25(OH)2D, and related hydroxylases as CYP27A1, CYP2R1 and CYP27B1 were lower in the degree I, II, and III obesity subgroups (P<.05), which were more disorder with the anthropological and clinical characteristics as the obesity was worsen in a BMI-independent manner (P<.05). However, there was a significant increase of CYP27B1 in the degree III obesity group than those in the degree I and II obesity subgroups. Furthermore, the methylation patterns on the genome-wide (Methylation/Hydroxymethylation) and VD metabolism genes (CYP27A1, CYP2R1 and CYP27B1) were negatively correlated with the worse obesity and their related expressions (P<.05). In summary, these results indicated that obesity could affect the homeostasis of VD metabolism related genes such as CYP27A1, CYP2R1, CYP27B1 and etc through abnormal DNA methylation, resulting in the disorders of VD related metabolites to decrease VD bio-availability with the BMI-independent manner. In turn, the lower levels of VD metabolites would affect the liver function to exacerbate the progression of obesity, as the Degree II and III obesity subgroups.

Abstract 2865: Efficacy of MDM2 and epigenetic inhibitors treatments for neuroblastoma

Abstract Pediatric Neuroblastoma (NB) is one of the most prevalent solid tumors in children that arise from embryonic neural crest cells and poses a significant challenge in the field of oncology. There are about 700 to 800 new cases of neuroblastoma diagnosed each year in the United States, and accounts for approximately 15% of all childhood cancer mortalities. Since this malignancy predominantly affects infants and young children, it is imperative to decipher the underlying molecular factors driving its pathogenesis. The novel molecular therapeutic approach includes the use of epigenetic modifiers as drugs. This approach aims to reverse significant epigenetic events underlying cancer pathogenesis, particularly abnormalities in histone modifications and DNA methylation. The reduction of both DNA and histone methylation levels leads to the reactivation of tumor suppressor genes and inhibits cancer cell proliferation and cell growth. In this study, we used selective and reversible small molecule agents such as MDM2 inhibitor (RG7388) and epigenetic modifiers (CM272 and SAHA) to block cell proliferation by inducing cell cycle arrest via enforcing Epigenetic alterations. Our initial experiments were designed to understand the effects of RG7388, CM272, and SAHA treatments on NB and their impact on cell cycle progression. It was hypothesized that the decrease in DNA methylation and increase in histone modification- augment p21 expression via the use of MDM2 inhibitors and epigenetic modifiers. To test this hypothesis, the NB cells (SK-N-SK and IMR-32) were treated with RG7388, CM272, and SAHA for 24 hours. The extent of Cell death was determined for NB cells by using the Trypan Blue Dye Exclusion (TBDE) method, and CellTiter-Glo® Luminescent Cell Viability Assay. Induction of apoptosis was determined by using the Immunofluorescence staining method with DEVD-amc substrate. The results of our study suggested that RG7388, CM272, and SAHA were able to induce cell death in the SK-N-SH cells following 24-hour treatment. Furthermore, we analyzed the levels of Tumor suppressor (p53), cell cycle arrest (p21, p27, AurkB, CDC25A, CyclinD) cell death (Bax, Bcl2, LC3, Beclin, PARP, Cleaved PARP, RIP1, RIP3, MLKL, p-AKT), and Epigenetic biomarker (DNMT1, DNMT3A, DNMT3B, acetyl histoneH3, H4, and H2b) protein expression levels using western blot analysis. The results showed significant elevation of p53, p21, p27, and acetylation of histone family biomarkers after treatment when compared with the control group. In summary, our results indicate that RG7388, CM272, and SAHA treatments can effectively induce cellular responses and prevent cell growth and progression by enforcing epigenetic changes in the NB cells. (This research was supported by the National Pediatric Cancer Foundation, Tampa, Florida, and the Royal Dames of Cancer Research Inc. of Ft. Lauderdale, Florida) Citation Format: Tahani Momenah, Umamaheswari Natarajan, Shyam Jaganathan, Appu Rathinavelu. Efficacy of MDM2 and epigenetic inhibitors treatments for neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2865.

Recent Insights into the Role of DNA Methylation and Histone Modifications in Systemic Sclerosis: A Scoping Review.

Systemic sclerosis is a complex idiopathic disease originating from an intricate interplay between genetic susceptibility, environmental factors, and epigenetic modifications. This scoping review aims to map the advancements made regarding DNA methylation abnormalities and histone modifications in systemic sclerosis in the past decade. A literature search was conducted using three electronic databases (Scopus, Web of Science and PubMed) to identify relevant articles. A total of 44 studies were selected for this review, demonstrating the critical contribution of epigenetic perturbations in multiple cell types to disease pathogenesis. In conclusion, this scoping review has elucidated the significant discoveries made in the past decade regarding the role of DNA methylation and histone modifications in systemic sclerosis. Further progress in the field could lead to the development of novel treatment possibilities targeting epigenetic marks.

Important role of DNA methylation hints at significant potential in tuberculosis.

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, has persisted as a major global public health threat for millennia. Until now, TB continues to challenge efforts aimed at controlling it, with drug resistance and latent infections being the two main factors hindering treatment efficacy. The scientific community is still striving to understand the underlying mechanisms behind Mtb's drug resistance and latent infection. DNA methylation, a critical epigenetic modification occurring throughout an individual's growth and development, has gained attention following advances in high-throughput sequencing technologies. Researchers have observed abnormal DNA methylation patterns in the host genome during Mtb infection. Given the escalating issue of drug-resistant Mtb, delving into the role of DNA methylation in TB's development is crucial. This review article explores DNA methylation's significance in human growth, development and disease, and its role in regulating Mtb's evolution and infection processes. Additionally, it discusses potential applications of DNA methylation research in tuberculosis.