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Schematic representation of DNA methylation patterning: The establishment of new DNA methylation patterns during development is regulated by the activity of de novo DNA methyltransferases, while activity of maintenance DNA methyltransferases serves to perpetuate these patterns during successive rounds of cell division. DNA methylation marks can be reversed through active or passive demethylation. Active demethylation involves the successive enzymatic oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC),5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) by TET (Ten-eleven translocation) dioxygenases, followed by thymine DNA glycosylase (TDG) dependent removal of 5fC and 5caC, coupled with base-excision repair to a cytosine (C). A hemi-methylated 5hmC is not recognized by the maintenance DNA methyltransferases and can get diluted and lost during replication, thus contributing to passive demethylation. Disruption of maintenance methyltransferase activity can similarly result in replication dependent dilution of DNA methylation.
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Pancreatic beta cells play a central role in regulating glucose homeostasis by secreting the hormone insulin. Failure of beta cells due to reduced function and mass and the resulting insulin insufficiency can drive the dysregulation of glycemic control, causing diabetes. Epigenetic regulation by DNA methylation is central to shaping the gene expres...
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In human type 2 diabetes, adipose tissue plays an important role in disturbing glucose homeostasis by secreting factors that affect the function of cells and tissues throughout the body, including insulin-producing pancreatic beta cells. We aimed here at studying the paracrine effect of stromal cells isolated from subcutaneous and omental adipose t...
Citations
... The HLA genes, as well as the other immuneregulating genes and molecules discussed earlier, are among these genes. Abnormal DNA methylation of genes involved in beta cell development, maturation, and differentiation as well as insulin synthesis can also predispose to T1DM (42). ...
Numerous suspect genes associated with type 1 diabetes mellitus (T1DM) have been identified, suggesting a need to focus on the disease's causal genes and mechanisms. This necessitates an update to raise public awareness. This review articulates genes with mutations that predispose individuals to T1DM. We conducted a comprehensive search of academic databases, including Web of Science, Scopus, PubMed, and Google Scholar, for relevant materials. Available information indicates that at least 70 genes are suspected in the pathogenesis of T1DM. However, the most frequently implicated genes include human leukocyte antigen (HLA), insulin (INS), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22 (PTPN22). Mutations or variants in these genes may lead to insulin insufficiency and, consequently, T1DM by tricking immune cells, such as T-cells and B-cells, into attacking self-antigens and triggering the autoimmunity of beta cells. Furthermore, this pathophysiology can be mediated through aberrant epigenetic modifications, including DNA methylation, histone post-translational modifications, and non-coding RNAs, in the mentioned genes. Some of these pathophysiologies are gene-specific and may have an epigenetic origin that is reversible. In the event of an epigenetic origin, a treatment for T1DM that addresses the causal genes or reverses epigenetic changes and their mechanisms could yield improved outcomes. Medical professionals are encouraged to design therapeutic regimens that specifically target the mentioned genes and address the identified epigenetic alterations in individuals expressing such etiologies.
... The establishment and maintenance of tissue-specific DNA methylation patterns is a crucial feature for mammalian development, and within the pancreas, DNA methylation plays a critical role in the specification of the endocrine and exocrine lineages [11,12]. To date, a systematic exploration of DNA methylation changes during human pancreas development has not been performed due to, at least in part, the paucity of tissue from fetal donors. ...
Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12864-024-10450-8.
... Non-coding RNA (ncRNA) is an epigenetic mechanism whereby a biologically active RNA molecule has undergone transcription but does not get translated or encode a protein [41]. ncRNAs include dicer-dependent microRNAs (miRNA) and short-interfering RNAs (siRNA), shaped by RNA interference pathways [42]. Literature suggests the presence of microRNAs in astrocytes that regulate glutamatergic and inflammatory signaling, which affect synaptic plasticity [43]. ...
Alzheimer's disease (AD) is a neurodegenerative condition that predominantly affects the hippocampus and the entorhinal complex, leading to memory lapse and cognitive impairment. This can have a negative impact on an individual's behavior, speech, and ability to navigate their surroundings. AD is one of the principal causes of dementia. One of the most accepted theories in AD, the amyloid β (Aβ) hypothesis, assumes that the buildup of the peptide Aβ is the root cause of AD. Impaired insulin signaling in the periphery and central nervous system has been considered to have an effect on the pathophysiology of AD. Further, researchers have shifted their focus to epigenetic mechanisms that are responsible for dysregulating major biochemical pathways and intracellular signaling processes responsible for directly or indirectly causing AD. The prime epigenetic mechanisms encompass DNA methylation, histone modifications, and non-coding RNA, and are majorly responsible for impairing insulin signaling both centrally and peripherally, thus leading to AD. In this review, we provide insights into the major epigenetic mechanisms involved in causing AD, such as DNA methylation and histone deacetylation. We decipher how the mechanisms alter peripheral insulin signaling and brain insulin signaling, leading to AD pathophysiology. In addition, this review also discusses the need for newer drug delivery systems for the targeted delivery of epigenetic drugs and explores targeted drug delivery systems such as nanoparticles, vesicular systems , networks, and other nano formulations in AD. Further, this review also sheds light on the future approaches used for epigenetic drug delivery.
... As previously discussed, this leads to genomic instability and increases mutation risk and other genomic abnormalities. Loss of DNA methylation at specific loci can even be used to calculate biological or methylation ages for cells or tissues; this can then be compared with chronological ages to measure relative rates of ageing as well as factors that influence it (Bell et al., 2019;Horvath & Raj, 2018 (Luttmer et al., 2013) and with the dysregulation of beta cells in diabetes (Parveen & Dhawan, 2021). Therefore, DNA hypomethylation is associated with cellular dysfunction and disease states. ...
DNA methylation controls DNA accessibility to transcription factors and other regulatory proteins, thereby affecting gene expression and hence cellular identity and function. As epigenetic modifications control the transcriptome, epigenetic dysfunction is strongly associated with pathological conditions and ageing. The development of pharmacological agents that modulate the activity of major epigenetic proteins are in pre‐clinical development and clinical use. However, recent publications have identified novel redox‐based signalling pathways, and therefore novel drug targets, that may exert epigenetic effects. This review will discuss the recent developments in nitric oxide (NO) signalling on DNA methylation as well as potential epigenetic drug targets that have emerged from the intersection of inflammation/redox biology and epigenetic regulation.
... Blood DNAm is often probed in epigenome-wide association studies (EWAS) to discover, test and validate biomarkers (Li et al., 2012;Locke et al., 2019;Mikeska and Craig, 2014) for diseases, such as type II diabetes (Bacos et al., 2016;Dayeh et al., 2016;Willmer et al., 2018), obesity (Samblas et al., 2019), non-alcoholic fatty liver disease (Hyun and Jung, 2020), asthma (Thibeault and Laprise, 2019) and dementia (Fransquet et al., 2020), as well as colorectal (Alizadeh-Sedigh et al., 2021;Dong and Ren, 2018;Jensen et al., 2019;Lin et al., 2021), esophageal (Yu et al., 2018), breast (Guan et al., 2019), pancreatic (Henriksen and Thorlacius-Ussing, 2021) and head-and-neck (Danstrup et al., 2020) cancers. It is widely used to study biological aging (Haftorn et al., 2021;Hannum et al., 2013;Horvath, 2013;Merid et al., 2020) and normal tissue epigenetics (Å senius et al., 2020;Huang et al., 2016), including development and function of the immune system (Parveen and Dhawan, 2021). Recent work studied how gestational age-related differential DNAm relates to fetal health and disease risk (Mayne et al., 2017;Merid et al., 2020). ...
Thousands of DNA methylation (DNAm) array samples from human blood are publicly available on the Gene Expression Omnibus (GEO), but they remain underutilized for experiment planning, replication and cross-study and cross-platform analyses. To facilitate these tasks, we augmented our recountmethylation R/Bioconductor package with 12 537 uniformly processed EPIC and HM450K blood samples on GEO as well as several new features. We subsequently used our updated package in several illustrative analyses, finding (i) study ID bias adjustment increased variation explained by biological and demographic variables, (ii) most variation in autosomal DNAm was explained by genetic ancestry and CD4+ T-cell fractions and (iii) the dependence of power to detect differential methylation on sample size was similar for each of peripheral blood mononuclear cells (PBMC), whole blood and umbilical cord blood. Finally, we used PBMC and whole blood to perform independent validations, and we recovered 38–46% of differentially methylated probes between sexes from two previously published epigenome-wide association studies.
Availability and implementation
Source code to reproduce the main results are available on GitHub (repo: recountmethylation_flexible-blood-analysis_manuscript; url: https://github.com/metamaden/recountmethylation_flexible-blood-analysis_manuscript). All data was publicly available and downloaded from the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/). Compilations of the analyzed public data can be accessed from the website recount.bio/data (preprocessed HM450K array data: https://recount.bio/data/remethdb_h5se-gm_epic_0-0-2_1589820348/; preprocessed EPIC array data: https://recount.bio/data/remethdb_h5se-gm_epic_0-0-2_1589820348/).
Supplementary information
Supplementary data are available at Bioinformatics Advances online.
... Cell-specific epigenomes respond to genetic, environmental, and metabolic signals, and they are linked to specific chromatin regions that control DNA accessibility to transcriptional factors that regulate gene expression and cellular states [1,2,4,5]. The epigenetic modifications include DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) [3,[6][7][8]. ...
... During this process, a methyl group (CH3) is transferred (covalently bound) to the C-5 position of the cytosine ring in a CpG dinucleotide. Thus, DNA methylation is a chemical change that affects cytosine residues and results in 5-methylcytosine formation (5 mC) [7,24,25]. DNA methylation is crucial for various processes during development, including maintaining genome stability by silencing repetitive elements and modulating tissue-specific and developmentally relevant gene expression patterns during cell division [26][27][28] (Figure 1). ...
... They (i.e., DNMT1, DNMT3A, and DNMT3B ) are canonical DNMTs that exhibit catalytic activity for establishing and maintaining the genomic methylation process. By contrast, DNMT2 and DNMT3L lack catalytic activity and play an allosteric regulatory role [7,[30][31][32]. Furthermore, DNMT2 is also an RNA methyltransferase, which methylates multiple tRNAs at cytosine 38 [33,34]. ...
Simple Summary
Epigenetics is a somatic, heritable pattern of gene expression or cellular phenotype mediated by structural changes in chromatin that occur without altering the DNA sequence. It is a key factor in determining gene expression levels and timing the response to endogenous and exogenous stimuli. Recent evidence suggests that epigenetics interact with the metabolic, endocrine, and immune response pathways. Accordingly, several enzymes that utilize vital metabolites as substrates or cofactors are employed in the catalysis of epigenetic modification. Consequently, alterations in metabolism may result in diseases and pathogenesis, such as endocrine disorders and cancer.
Abstract
Each cell in a multicellular organism has its own phenotype despite sharing the same genome. Epigenetics is a somatic, heritable pattern of gene expression or cellular phenotype mediated by structural changes in chromatin that occur without altering the DNA sequence. Epigenetic modification is an important factor in determining the level and timing of gene expression in response to endogenous and exogenous stimuli. There is also growing evidence concerning the interaction between epigenetics and metabolism. Accordingly, several enzymes that consume vital metabolites as substrates or cofactors are used during the catalysis of epigenetic modification. Therefore, altered metabolism might lead to diseases and pathogenesis, including endocrine disorders and cancer. In addition, it has been demonstrated that epigenetic modification influences the endocrine system and immune response-related pathways. In this regard, epigenetic modification may impact the levels of hormones that are important in regulating growth, development, reproduction, energy balance, and metabolism. Altering the function of the endocrine system has negative health consequences. Furthermore, endocrine disruptors (EDC) have a significant impact on the endocrine system, causing the abnormal functioning of hormones and their receptors, resulting in various diseases and disorders. Overall, this review focuses on the impact of epigenetics on the endocrine system and its interaction with metabolism.
... CpG dinucleotides (CpG islands) are distributed invariably throughout the genome and are the prime spots of DNA methylation in the human genome [61,62]. In early embryonic stage, 60% of tissue-specific differentially methylated regions are methylated however, de-methylation occurs when embryonic cells transform into adult tissues [63,64]. ...
Non-invasive prenatal screening (NIPS) offers an opportunity to screen or determine features associated with the fetus. Earlier, prenatal testing was done with cytogenetic procedures like karyotyping or fluorescence in-situ hybridization, which necessitated invasive methods such as fetal blood sampling, chorionic villus sampling or amniocentesis. Over the last two decades, there has been a paradigm shift away from invasive prenatal diagnostic methods to non-invasive ones. NIPS tests heavily rely on cell-free fetal DNA (cffDNA). This DNA is released into the maternal circulation by placenta. Like cffDNA, fetal cells such as nucleated red blood cells, placental trophoblasts, leukocytes, and exosomes or fetal RNA circulating in maternal plasma, have enormous potential in non-invasive prenatal testing, but their use is still limited due to a number of limitations. Non-invasive approaches currently use circulating fetal DNA to assess the fetal genetic milieu. Methods with an acceptable detection rate and specificity such as sequencing, methylation, or PCR, have recently gained popularity in NIPS. Now that NIPS has established clinical significance in prenatal screening and diagnosis, it is critical to gain insights into and comprehend the genesis of NIPS de novo. The current review reappraises the development and emergence of non-invasive prenatal screen/test approaches, as well as their clinical application, with a focus, on the scope, benefits, and limitations.
... Epigenetic mechanisms, such as DNA methylation, mediate context-specific changes in gene expression to direct the progressive refinement of cell fates during development (3). DNA methylation is the best-studied epigenetic module, with the de novo DNA methyltransferases Dnmt3a and Dnmt3b establishing new methylation patterns, whereas Dnmt1 maintains and propagates existing patterns through cell division (4). Modulation of DNA methylation patterns is known to dictate cell fate choices. ...
... The large-scale changes in human islet methylome associated with b-cell identity and function genes in type 2 diabetes strengthen this idea (50). Our data suggest that embryonic DNA-methylation patterning may affect postnatal b-cell identity, which is noteworthy, given that over-or undernutrition during development can predispose to risk of b-cell failure (4). Future work will identify the specific aspects of postnatal b-cell phenotype that rely upon embryonic epigenetic patterning and will elucidate the significance of such a paradigm. ...
The molecular and functional heterogeneity of pancreatic β-cells is well recognized, but the underlying mechanisms remain unclear. Pancreatic islets harbor a subset of β-cells that co-express Tyrosine Hydroxylase (TH), an enzyme involved in synthesis of catecholamines that repress insulin secretion. Restriction of the TH+ β-cells within islets is essential for appropriate function in mice, such that higher proportion of these cells corresponds to reduced insulin secretion. Here, we use these cells as a model to dissect the developmental control of β-cell heterogeneity. We define the specific molecular and metabolic characteristics of TH+ β-cells, and show differences in their developmental restriction in mice and humans. We show that TH expression in β-cells is restricted by DNA methylation during β-cell differentiation. Ablation of de novo DNA methyltransferase Dnmt3a in the embryonic progenitors results in a dramatic increase in the proportion of TH+ β-cells, while β-cell specific ablation of Dnmt3a does not. We demonstrate that maintenance of Th promoter methylation is essential for its continued restriction in postnatal β-cells. Loss of Th promoter methylation in response to chronic overnutrition increases the number of TH+ β-cells, corresponding to impaired β-cell function. These results reveal a regulatory role of DNA methylation in determining β-cell heterogeneity.
... The adaptation of cellular response to changing nutrient cues at the transcriptional level involves the epigenome. Epigenetic dysregulation has been identified as a major player underlying b-cell defects as well as the dysfunction of peripheral insulin-sensitive tissues in diabetes (16)(17)(18). Chronic exposure to a particular metabolic state (such as hyperglycemia) can induce irreversible epigenetic and functional changes that persist even after cessation of the exposure (19). This phenomenon of "metabolic memory" could be pertinent to adverse outcomes associated with weight cycling. ...
... In addition, DNA methylation-mediated repression of glucose-secretion decoupling genes to modulate GSIS was conserved in human β cells. Thus, epigenetic regulation by DNA methylation plays a central role in shaping the gene expression patterns that define the fully functional β cell phenotype and regulate β cell growth [268]. The specificity of DNA methylation patterning is ensured by the interaction of DNMT3A with transcription factors NKX2.2 and NKX6.1, allowing recruitment to spe-cific sites. ...
... The specificity of DNA methylation patterning is ensured by the interaction of DNMT3A with transcription factors NKX2.2 and NKX6.1, allowing recruitment to spe-cific sites. Once established, the β cell specific DNA methylation patterns are maintained by the maintenance methyltransferase DNMT1 [268]. It has been known for a decade that ERRγ functions as a transcriptional activator of mouse and human DNMT1 expression by direct binding to its response elements (ERE1/ERE2) in the DNMT1 promoters [269]. ...
Pancreatic β cell expansion and functional maturation during the birth-to-weaning period is driven by epigenetic programs primarily triggered by growth factors, hormones, and nutrients provided by human milk. As shown recently, exosomes derived from various origins interact with β cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic β cell programming during the postnatal period of lactation as well as during continuous cow milk exposure of adult humans to bovine MEX. Mechanistic evidence suggests that MEX miRs stimulate mTORC1/c-MYC-dependent postnatal β cell proliferation and glycolysis, but attenuate β cell differentiation, mitochondrial function, and insulin synthesis and secretion. MEX miR content is negatively affected by maternal obesity, gestational diabetes, psychological stress, caesarean delivery, and is completely absent in infant formula. Weaning-related disappearance of MEX miRs may be the critical event switching β cells from proliferation to TGF-β/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse β cell differentiation, promoting β cell de-differentiation. Whereas MEX miR signaling supports postnatal β cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate β cells back to the postnatal phenotype (diabetes induction).
