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European Journal of Endocrinology Dec 2023Pseudohypoparathyroidism type 1B (PHP1B) caused by methylation defects of differentially methylated regions (DMRs) on the GNAS locus can be categorized into groups...
OBJECTIVE
Pseudohypoparathyroidism type 1B (PHP1B) caused by methylation defects of differentially methylated regions (DMRs) on the GNAS locus can be categorized into groups according to etiologies and methylation defect patterns of the DMRs. The aim of this study was to clarify the clinical characteristics of each group.
DESIGN
Comprehensive molecular analyses consisting of methylation, copy number, and microsatellite analyses.
METHODS
Eighty-four patients with PHP1B were included in this study. We classified them into 5 groups, namely, autosomal dominant inheritance-PHP1B (Group 1, G1), sporadic-PHP1B (G2), and atypical-PHP1B (G3-G5), based on the methylation defect patterns in 4 DMRs on the GNAS locus and etiologies and evaluated the clinical findings in each group and compared them among the groups.
RESULTS
G2 had the youngest age and the highest serum intact parathyroid hormone levels among the 5 groups at the time of diagnosis. The most common symptoms at the time of diagnosis were tetany in G1, and seizures or loss of consciousness in G2. Albright's hereditary osteodystrophy and PHP-suggestive features were most frequently observed in the G2 proband. Nine patients had neurodevelopmental disorders (NDs) consisting of mild to borderline intellectual disability and/or developmental delay. There were no significant correlations between the average methylation ratios of 7 CpG sites in the GNAS-A/B:TSS-DMR and hormonal and biochemical findings.
CONCLUSION
This study revealed the differences in some clinical characteristics, particularly clinical features, and ages at the time of diagnosis between G2 and other groups and detailed NDs observed in some patients with PHP1B.
Topics: Humans; GTP-Binding Protein alpha Subunits, Gs; Chromogranins; Pseudohypoparathyroidism; Family; DNA Methylation
PubMed: 38039118
DOI: 10.1093/ejendo/lvad163 -
International Journal of Molecular... Nov 2023Epigenetic aging is a hot topic in the field of aging research. The present study estimated epigenetic age in long-lived individuals, who are currently actively being...
Epigenetic aging is a hot topic in the field of aging research. The present study estimated epigenetic age in long-lived individuals, who are currently actively being studied worldwide as an example of successful aging due to their longevity. We used Bekaert's blood-based age prediction model to estimate the epigenetic age of 50 conditionally "healthy" and 45 frail long-livers over 90 years old. Frailty assessment in long-livers was conducted using the Frailty Index. The control group was composed of 32 healthy individuals aged 20-60 years. The DNA methylation status of 4 CpG sites ( CpG1, CpG1, CpG6, and CpG1) included in the epigenetic clock was assessed through pyrosequencing. According to the model calculations, the epigenetic age of long-livers was significantly lower than their chronological age (on average by 21 years) compared with data from the group of people aged 20 to 60 years. This suggests a slowing of epigenetic and potentially biological aging in long livers. At the same time, the obtained results showed no statistically significant differences in delta age (difference between the predicted and chronological age) between "healthy" long livers and long livers with frailty. We also failed to detect sex differences in epigenetic age either in the group of long livers or in the control group. It is possible that the predictive power of epigenetic clocks based on a small number of CpG sites is insufficient to detect such differences. Nevertheless, this study underscores the need for further research on the epigenetic status of centenarians to gain a deeper understanding of the factors contributing to delayed aging in this population.
Topics: Aged, 80 and over; Humans; Female; Male; Epigenesis, Genetic; Frailty; Aging; Longevity; DNA Methylation; CpG Islands
PubMed: 38069189
DOI: 10.3390/ijms242316867 -
Scientific Reports Sep 2023Circulating tumor cells (CTCs) and epigenetic alterations are involved in the development of metastasis from solid tumors, such as colorectal cancer (CRC). The aim of...
Circulating tumor cells (CTCs) and epigenetic alterations are involved in the development of metastasis from solid tumors, such as colorectal cancer (CRC). The aim of this study was to characterize the DNA methylation profile of metastasis-competent CTCs in CRC. The DNA methylome of the human CRC-derived cell line CTC-MCC-41 was analyzed and compared with primary (HT29, Caco2, HCT116, RKO) and metastatic (SW620 and COLO205) CRC cells. The association between methylation and the transcriptional profile of CTC-MCC-41 was also evaluated. Differentially methylated CpGs were validated with pyrosequencing and qMSP. Compared to primary and metastatic CRC cells, the methylation profile of CTC-MCC-41 was globally different and characterized by a slight predominance of hypomethylated CpGs mainly distributed in CpG-poor regions. Promoter CpG islands and shore regions of CTC-MCC-41 displayed a unique methylation profile that was associated with the transcriptional program and relevant cancer pathways, mainly Wnt signaling. The epigenetic regulation of relevant genes in CTC-MCC-41 was validated. This study provides new insights into the epigenomic landscape of metastasis-competent CTCs, revealing biological information for metastasis development, as well as new potential biomarkers and therapeutic targets for CRC patients.
Topics: Humans; Neoplastic Cells, Circulating; DNA Methylation; Caco-2 Cells; Epigenesis, Genetic; Epigenomics; Colonic Neoplasms
PubMed: 37717096
DOI: 10.1038/s41598-023-42037-w -
Journal of Molecular Medicine (Berlin,... May 2024Genomic instability and epigenetic alterations are some of the prominent factors affecting aging. Age-related heterochromatin loss and decreased whole-genome DNA... (Review)
Review
Genomic instability and epigenetic alterations are some of the prominent factors affecting aging. Age-related heterochromatin loss and decreased whole-genome DNA methylation are associated with abnormal gene expression, leading to diseases and genomic instability. Modulation of these epigenetic changes is crucial for preserving genomic integrity and controlling cellular identity is important for slowing the aging process. Numerous studies have shown that caloric restriction is the gold standard for promoting longevity and healthy aging in various species ranging from rodents to primates. It can be inferred that delaying of aging through the main effector such as calorie restriction is involved in cellular identity and epigenetic modification. Thus, an understanding of aging through calorie restriction may seek a more in-depth understanding. In this review, we discuss how caloric restriction promotes longevity and healthy aging through genomic stability and epigenetic alterations. We have also highlighted how the effectors of caloric restriction are involved in modulating the chromatin-based barriers.
Topics: Caloric Restriction; Humans; Epigenesis, Genetic; Animals; Aging; Longevity; DNA Methylation; Genomic Instability
PubMed: 38456926
DOI: 10.1007/s00109-024-02430-y -
JAMA Network Open Oct 2023Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and appears to have disproportionately higher incidence and worse outcomes among...
IMPORTANCE
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and appears to have disproportionately higher incidence and worse outcomes among younger African American females.
OBJECTIVE
To investigate whether epigenetic differences exist in TNBCs of younger African American females that may explain clinical disparities seen in this patient group.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study used clinical, demographic, DNA methylation (HumanMethylation450; Illumina), and gene expression (RNA sequencing) data for US patient populations from publicly available data repositories (The Cancer Genome Atlas [TCGA], 2006-2012, and Gene Expression Omnibus [GEO], 2004-2013) accessed on April 13, 2021. White and African American females with TNBC identified in TCGA (69 patients) and a validation cohort of 210 African American patients from GEO (GSE142102) were included. Patients without available race or age data were excluded. Data were analyzed from September 2022 through April 2023.
MAIN OUTCOMES AND MEASURES
DNA methylation and gene expression profiles of TNBC tumors by race (self-reported) and age were assessed. Age was considered a dichotomous variable using age 50 years as the cutoff (younger [<50 years] vs older [≥50 years]).
RESULTS
A total of 69 female patients (34 African American [49.3%] and 35 White [50.7%]; mean [SD; range] age, 55.7 [11.6; 29-82] years) with TNBC were included in the DNA methylation analysis; these patients and 210 patients in the validation cohort were included in the gene expression analysis (279 patients). There were 1115 differentially methylated sites among younger African American females. The DNA methylation landscape on TNBC tumors in this population had increased odds of enrichment of hormone (odds ratio [OR], 1.82; 95% CI, 1.21 to 2.67; P = .003), muscle (OR, 1.85; 95% CI, 1.44 to 2.36; P < .001), and proliferation (OR, 3.14; 95% CI, 2.71 to 3.64; P < .001) pathways vs other groups (older African American females and all White females). Alterations in regulators of these molecular features in TNBCs of younger African American females were identified involving hormone modulation (downregulation of androgen receptor: fold change [FC] = -2.93; 95% CI, -4.76 to -2.11; P < .001) and upregulation of estrogen-related receptor α (FC = 0.86; 95% CI, 0.34 to 1.38; P = .002), muscle metabolism (upregulation of FOXC1: FC = 1.33; 95% CI, 0.62 to 2.03; P < .001), and proliferation mediators (upregulation of NOTCH1: FC = 0.71; 95% CI, 0.23 to 1.19; P = .004 and MYC (FC = 0.81; 95% CI, 0.18 to 1.45; P = .01).
CONCLUSIONS AND RELEVANCE
These findings suggest that TNBC of younger African American females may represent a distinct epigenetic entity and offer novel insight into molecular alterations associated with TNBCs of this population. Understanding these epigenetic differences may lead to the development of more effective therapies for younger African American females, who have the highest incidence and worst outcomes from TNBC of any patient group.
Topics: Female; Humans; Middle Aged; Black or African American; Cross-Sectional Studies; Hormones; Triple Negative Breast Neoplasms; White; Epigenesis, Genetic; Adult; Aged; Aged, 80 and over
PubMed: 37796506
DOI: 10.1001/jamanetworkopen.2023.35821 -
Environment International Aug 2023Native American communities suffer disproportionately from elevated metal exposures and increased risk for cardiovascular diseases and diabetes. DNA methylation is a...
INTRODUCTION
Native American communities suffer disproportionately from elevated metal exposures and increased risk for cardiovascular diseases and diabetes. DNA methylation is a sensitive biomarker of aging-related processes and novel epigenetic-based "clocks" can be used to estimate accelerated biological aging that may underlie increased risk. Metals alter DNA methylation, yet little is known about their individual and combined impact on epigenetic age acceleration. Our objective was to investigate the associations of metals on several DNA methylation-based aging measures in the Strong Heart Study (SHS) cohort.
METHODS
Blood DNA methylation data from 2,301 SHS participants was used to calculate age acceleration of epigenetic clocks (PhenoAge, GrimAge, DunedinPACE, Hannum, Horvath). Urinary metals [arsenic (As), cadmium (Cd), tungsten (W), zinc (Zn), selenium (Se), molybdenum (Mo)] were creatinine-adjusted and categorized into quartiles. We examined associations of individual metals through linear regression models and used Bayesian Kernel Machine Regression (BKMR) for the impact of the total metal mixture on epigenetic age acceleration.
RESULTS
The mixture of nonessential metals (W, As, Cd) was associated with greater GrimAge acceleration and DunedinPACE, while the essential metal mixture (Se, Zn, Mo) was associated with lower epigenetic age acceleration. Cd was associated with increased epigenetic age acceleration across all clocks and BKMR analysis suggested nonlinear associations between Se and DunedinPACE, GrimAge, and PhenoAge acceleration. No interactions between individual metals were observed. The associations between Cd, Zn, and epigenetic age acceleration were greater in never smokers in comparison to current/former smokers.
CONCLUSION
Nonessential metals were positively associated with greater epigenetic age acceleration, with strongest associations observed between Cd and DunedinPACE and GrimAge acceleration. In contrast, essential metals were associated with lower epigenetic aging. Examining the influence of metal mixtures on epigenetic age acceleration can provide insight into metals and aging-related diseases.
Topics: Humans; Aging; American Indian or Alaska Native; Arsenic; Bayes Theorem; Cadmium; DNA Methylation; Epigenesis, Genetic; Metals; Selenium; Zinc
PubMed: 37364305
DOI: 10.1016/j.envint.2023.108064 -
International Journal of Biological... Dec 2023RNA methylation, an epigenetic modification that does not alter gene sequence, may be important to diverse biological processes. Protein regulators of RNA methylation... (Review)
Review
RNA methylation, an epigenetic modification that does not alter gene sequence, may be important to diverse biological processes. Protein regulators of RNA methylation include "writers," "erasers," and "readers," which respectively deposit, remove, and recognize methylated RNA. RNA methylation, particularly N6-methyladenosine (m6A), 5-methylcytosine (m5C), N3-methylcytosine (m3C), N1-methyladenosine (m1A) and N7-methylguanosine (m7G), has been suggested as disease therapeutic targets. Despite advances in the structure and pharmacology of RNA methylation regulators that have improved drug discovery, regulating these proteins by various post-translational modifications (PTMs) has received little attention. PTM modifies protein structure and function, affecting all aspects of normal biology and pathogenesis, including immunology, cell differentiation, DNA damage repair, and tumors. It is becoming evident that RNA methylation regulators are also regulated by diverse PTMs. PTM of RNA methylation regulators induces their covalent linkage to new functional groups, hence modifying their activity and function. Mass spectrometry has identified many PTMs on protein regulators of RNA methylation. In this review, we describe the functions and PTM of protein regulators of RNA methylation and summarize the recent advances in the regulatory mode of human disease and its underlying mechanisms.
Topics: Humans; Methylation; RNA; Epigenesis, Genetic; Protein Processing, Post-Translational; Cell Differentiation
PubMed: 37690652
DOI: 10.1016/j.ijbiomac.2023.126773 -
Journal of Biomolecular Structure &... Apr 2024The switching on or off of methylation, a change from a normal methylation to hyper or hypo methylation is implicated in many diseases that include cancers, infectious,...
The switching on or off of methylation, a change from a normal methylation to hyper or hypo methylation is implicated in many diseases that include cancers, infectious, neurodegenerative diseases and others. Methyltransferases are one of the most sought targets that have diversified for the methylation of a variety of substrates. However, without S-adenosyl-l-methionine (SAM), the universal methyl donor, the majority of the methyltransferases remain functionally inactive. In this article, we did a comprehensive analysis of all available SAM-receptor crystal structures at atom, moiety and structure levels to gain deeper insights into the structure and function of SAM. SAM demonstrated flexibility in binding to a variety of receptors irrespective of the size of the binding pockets. Further analysis of the binding pockets resulted in all SAM conformations clustering into four natural shapes. The conserved interaction analysis provides an unambiguous orientation of SAM binding to receptors which has been elusive till now. SAM peptide moiety (SPM) and SAM nucleobase moiety (SNM) show up to 89% interactions with receptors whereas only 11% interactions with SAM ribose moiety (SRM). It is found that SPM and SNM terminal atoms anchor to the highly conserved receptor subsites creating a workbench for catalysis. It is seen that every interacting atom and its position is crucial in the methyl transfer phenomenon. A very unique observation is that the methyl group of SAM does not have even one interaction with the receptor. The deep insights gained help in the design and development of novel drugs against the methyltransferases.Communicated by Ramaswamy H. Sarma.
Topics: Methyltransferases; S-Adenosylmethionine; Methylation; Catalysis
PubMed: 37261836
DOI: 10.1080/07391102.2023.2217679 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Nov 2023Methylation plays a vital role in biological systems. SAM (-adenosyl-L-methionine), an abundant cofactor in life, acts as a methyl donor in most biological methylation... (Review)
Review
Methylation plays a vital role in biological systems. SAM (-adenosyl-L-methionine), an abundant cofactor in life, acts as a methyl donor in most biological methylation reactions. SAM-dependent methyltransferases (MTase) transfer a methyl group from SAM to substrates, thereby altering their physicochemical properties or biological activities. In recent years, many SAM analogues with alternative methyl substituents have been synthesized and applied to methyltransferases that specifically transfer different groups to the substrates. These include functional groups for labeling experiments and novel alkyl modifications. This review summarizes the recent progress in the synthesis and application of SAM methyl analogues and prospects for future research directions in this field.
Topics: S-Adenosylmethionine; Methionine; Methyltransferases; Methylation; Racemethionine
PubMed: 38013176
DOI: 10.13345/j.cjb.230271 -
Clinical Epigenetics Oct 2023Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and...
BACKGROUND
Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced DNAm changes in airway epithelial cells, and assess potential functional consequences and the influence of genetic variation and asthma-related clinical variables.
RESULTS
We followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study using paired nasal epithelial cultures from Puerto Rican children (n = 97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p < 9 × 10). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p value = 3.3 × 10). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR] < 0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p = 0.030). DNAm changes in these three CpGs were shown to be influenced by three independent genetic variants (FDR < 0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30 × 10 ≤ p ≤ 6.60 × 10). Additionally, hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with increased gene expression of the genes where they are located (FDR < 0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p = 0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p value < 0.05).
CONCLUSIONS
This study revealed evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma.
Topics: Child; Humans; DNA Methylation; Epigenomics; Asthma; Albuterol; Epigenesis, Genetic; Bronchodilator Agents; Epithelial Cells; Genome-Wide Association Study
PubMed: 37784136
DOI: 10.1186/s13148-023-01571-0