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Gliomas, the most common type of malignant primary brain tumor, were conventionally classified through WHO Grades I-IV (now 1-4), with low-grade gliomas being entities belonging to Grades 1 or 2. While the focus of the WHO Classification for Central Nervous System (CNS) tumors had historically been on histopathological attributes, the recently released fifth edition of the classification (WHO CNS5) characterizes brain tumors, including gliomas, using an integration of histological and molecular features, including their epigenetic changes such as histone methylation, DNA methylation, and histone acetylation, which are increasingly being used for the classification of low-grade gliomas. This review describes the current understanding of the role of DNA methylation, demethylation, and histone modification in pathogenesis, clinical behavior, and outcomes of brain tumors, in particular of low-grade gliomas. The review also highlights potential diagnostic and/or therapeutic targets in associated cellular biomolecules, structures, and processes. Targeting of MGMT promoter methylation, TET-hTDG-BER pathway, association of G-CIMP with key gene mutations, PARP inhibition, IDH and 2-HG-associated processes, TERT mutation and ARL9-associated pathways, DNA Methyltransferase (DNMT) inhibition, Histone Deacetylase (HDAC) inhibition, BET inhibition, CpG site DNA methylation signatures, along with others, present exciting avenues for translational research. This review also summarizes the current clinical trial landscape associated with the therapeutic utility of epigenetics in low-grade gliomas. Much of the evidence currently remains restricted to preclinical studies, warranting further investigation to demonstrate true clinical utility.

Background: Late onset dementia due to Alzheimer's disease (AD) has a sex‐biased incidence with females comprising nearly two thirds of all cases. Females have a more rapid progression in cognitive decline and higher levels of known AD biomarker pathology compared to men. Genetic sequence variation does not account for the sex‐biased incidence of AD, directing attention to the emerging role of epigenetics in AD. Using whole genome methylation sequencing (WGMS), we previously reported 28,038 differentially methylated position (DMPs) within 2,707 genes between persons with and without AD. Here we report sex‐specific DNA methylation levels in AD. Method: WGMS data quantified DNA methylation levels at 25,406,945 CpG loci in 281 blood samples from 109 AD (47 female, 62 male) and 174 cognitively unimpaired (CU) individuals (90 female, 84 male) in the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention cohorts. Beta‐binomial regression models were developed to test for significant sex‐specific DNA methylation levels between CU and AD accounting for batch effects, estimated white blood cell proportions, BMI, and age. P‐values were corrected and local false discovery rates (lFDRs) were calculated. Result: 13,293 DMPs were identified in females and 20,719 DMPs were identified in males (Figure 1) when comparing CU and AD (lFDR < 0.05; mean methylation difference > 2.5%). Approximately 2% (280) of the DMPs overlap between sexes with 87 having opposite mean methylation differences. The majority of DMPs annotate to introns (55.9% females; 54.8% males) with most of the remainder intergenic (37.0% females; 37.9% males). Annotation of DMPs to genes identified 1,498 genes that are only differentially methylated in females, and 2,183 genes that are only differentially methylated in males, with 1,365 differentially methylated genes shared between females and males (Figure 2). Gene ontological analyses identified significant enrichment of pathways related to glutamate receptor and ion channel activity in shared gene sets (Figure 3). Conclusion: 33,732 unique, sex‐specific DMPs in AD were identified with more than 60% annotated to one of 5,067 genes. DMP‐associated genes have sex‐specific DNA methylation levels suggesting that these DMPs may play a role in the biased pathogenesis of AD. [ABSTRACT FROM AUTHOR]

In mammals, the molecular mechanisms underlying transgenerational inheritance of phenotypic traits in serial generations of progeny after ancestral environmental exposures, without variation in DNA sequence, remain elusive. We've recently described transmission of a beneficial trait in rats and mice, in which F0 supplementation of methyl donors, including folic acid, generates enhanced axon regeneration after sharp spinal cord injury in untreated F1 to F3 progeny linked to differential DNA methylation levels in spinal cord tissue. To test whether the transgenerational effect of folic acid is transmitted via the germline, we performed whole-genome methylation sequencing on sperm DNA from F0 mice treated with either folic acid or vehicle control, and their F1, F2, and F3 untreated progeny. Transgenerational differentially methylated regions (DMRs) are observed in each consecutive generation and distinguish folic acid from untreated lineages, predominate outside of CpG islands and in regions of the genome that regulate gene expression, including promoters, and overlap at both the differentially methylated position (DMP) and gene levels. These findings indicate that molecular changes between generations are caused by ancestral folate supplementation. In addition, 29,719 DMPs exhibit serial increases or decreases in DNA methylation levels in successive generations of untreated offspring, correlating with a serial increase in the phenotype across generations, consistent with a 'wash-in' effect. Sibship-specific DMPs annotate to genes that participate in axon- and synapse-related pathways. [ABSTRACT FROM AUTHOR]

Background: DNA microarray‐based studies report differentially methylated positions (DMPs) in blood between cognitively unimpaired persons (CU) and persons with late‐onset dementia due to Alzheimer's disease (AD) or Mild Cognitive Impairment (MCI) but interrogate less than 4% of the human genome. Whole genome methylation sequencing (WGMS) quantifies DNA methylation levels across the entire human genome (>25 million CpG loci). Using WGMS, we previously reported 28,038 DMPs within 2,707 genes between persons with and without AD. Method: We used WGMS to measure DNA methylation levels in nuclear genes encoding proteins that participate in mitochondrial function as cataloged in the Human Protein Atlas in blood samples from participants with AD (N = 109) and MCI (N = 99) compared to CU (N = 174). DNA methylation levels were compared cross‐sectionally in the Wisconsin Alzheimer's Disease Research Center (WADRC) and the Wisconsin Registry for Alzheimer's Prevention (WRAP) cohorts. ParticipantAPOE allele and demographic information are provided in Table 1. Result: Mitochondrial‐related genes (N = 1,121) were differentially methylated (local false discovery rate [lFDR] < 0.01) in persons with AD (N = 218) and MCI (N = 421) compared to CU controls. Gene ontology pathway analyses of differentially methylated genes observed in both AD and MCI groups (N = 142) are enriched for multiple terms, including myristoyl‐CoA hydrolase, palmitoyl‐CoA hydrolase, and thiolester hydrolase activity (Figure 1). Differentially methylated genes align with differentially expressed genes that support beta‐oxidation (acyl‐CoA dehydrogenase family member 9 [ACAD9]) and fatty acid transport into mitochondria (carnitine palmitoyl transferase I [CPT1A]) in blood from persons with AD. Conclusion: Disordered pathways that participate in beta‐oxidation and fatty acid metabolism have been identified in large‐scale multi‐omic reports of AD histopathology. Present data indicate that corresponding changes in the methylome play a role in mitochondrial pathways known to contribute to the pathogenesis of AD and may serve as candidates for diagnosis and intervention. [ABSTRACT FROM AUTHOR]

Children with an anxious temperament (AT) are at a substantially increased risk to develop anxiety and depression. The young rhesus monkey is ideal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. Heritability, functional imaging, and gene expression studies of AT in young monkeys revealed that the central nucleus of the amygdala (Ce) is a key environmentally sensitive substrate of this at risk phenotype. Because epigenetic marks (e.g., DNA methylation) can be modulated by environmental stimuli, these data led us to hypothesize a role for DNA methylation in the development of AT. To test this hypothesis, we used reduced representation bisulfite sequencing to examine the cross-sectional genome-wide methylation levels in the Ce of 23 age-matched monkeys (1.3 ± 0.2 years) phenotyped for AT. Because AT reflects a continuous trait-like variable, we used an analytical approach that is consistent with this biology to identify genes in the Ce with methylation patterns that predict AT. Expression data from the Ce of these same monkeys were then used to find differentially methylated candidates linked to altered gene regulation. Two genes particularly relevant to the AT phenotype were BCL11A and JAG1. These transcripts have well-defined roles in neurodevelopmental processes, including neurite arborization and the regulation of neurogenesis. Together, these findings represent a critical step toward understanding the effects of early environment on the neuromolecular mechanisms that underlie the risk to develop anxiety and depressive disorders.

INTRODUCTION: DNA microarray‐based studies report differentially methylated positions (DMPs) in blood between late‐onset dementia due to Alzheimer's disease (AD) and cognitively unimpaired individuals, but interrogate < 4% of the genome. METHODS: We used whole genome methylation sequencing (WGMS) to quantify DNA methylation levels at 25,409,826 CpG loci in 281 blood samples from 108 AD and 173 cognitively unimpaired individuals. RESULTS: WGMS identified 28,038 DMPs throughout the human methylome, including 2707 differentially methylated genes (e.g., SORCS3, GABA, and PICALM) encoding proteins in biological pathways relevant to AD such as synaptic membrane, cation channel complex, and glutamatergic synapse. One hundred seventy‐three differentially methylated blood‐specific enhancers interact with the promoters of 95 genes that are differentially expressed in blood from persons with and without AD. DISCUSSION: WGMS identifies differentially methylated CpGs in known and newly detected genes and enhancers in blood from persons with and without AD. Highlights: Whole genome DNA methylation levels were quantified in blood from persons with and without Alzheimer's disease (AD).Twenty‐eight thousand thirty‐eight differentially methylated positions (DMPs) were identified.Two thousand seven hundred seven genes comprise DMPs.Forty‐eight of 75 independent genetic risk loci for AD have DMPs.One thousand five hundred sixty‐eight blood‐specific enhancers comprise DMPs, 173 of which interact with the promoters of 95 genes that are differentially expressed in blood from persons with and without AD. [ABSTRACT FROM AUTHOR]

Over the last years, the use of peripheral blood-derived big datasets in combination with machine learning technology has accelerated the understanding, prediction, and management of pulmonary and critical care conditions. The goal of this article is to provide readers with an introduction to the methods and applications of blood omics and other multiplex-based technologies in the pulmonary and critical care medicine setting to better appreciate the current literature in the field. To accomplish that, we provide essential concepts needed to rationalize this approach and introduce readers to the types of molecules that can be obtained from the circulating blood to generate big datasets; elaborate on the differences between bulk, sorted, and single-cell approaches; and the basic analytical pipelines required for clinical interpretation. Examples of peripheral blood-derived big datasets used in recent literature are presented, and limitations of that technology are highlighted to qualify both the current and future value of these methodologies. [ABSTRACT FROM AUTHOR]

Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans. [ABSTRACT FROM AUTHOR]

Maternal malnutrition remains one of the major adversities affecting brain development and long-term mental health outcomes, increasing the risk to develop anxiety and depressive disorders. We have previously shown that malnutrition-induced anxiety-like behaviours can be rescued by a social and sensory stimulation (enriched environment) in male mice. Here, we expand these findings to adult female mice and profiled genome-wide ventral hippocampal 5hmC levels related to malnutrition-induced anxiety-like behaviours and their rescue by an enriched environment. This approach revealed 508 differentially hydroxymethylated genes associated with protein malnutrition and that several genes (N = 34) exhibited a restored 5hmC abundance to control levels following exposure to an enriched environment, including genes involved in neuronal functions like dendrite outgrowth, axon guidance, and maintenance of neuronal circuits (e.g. Fltr3, Itsn1, Lman1, Lsamp, Nav, and Ror1) and epigenetic mechanisms (e.g. Hdac9 and Dicer1). Sequence motif predictions indicated that 5hmC may be modulating the binding of transcription factors for several of these transcripts, suggesting a regulatory role for 5hmC in response to perinatal malnutrition and exposure to an enriched environment. Together, these findings establish a role for 5hmC in early-life malnutrition and reveal genes linked to malnutrition-induced anxious behaviours that are mitigated by an enriched environment. [ABSTRACT FROM AUTHOR]

Alterations in environmentally sensitive epigenetic mechanisms (e.g., DNA methylation) influence axonal regeneration in the spinal cord following sharp injury. Conventional DNA methylation detection methods using sodium bisulphite treatment do not distinguish between methylated and hydroxymethylated forms of cytosine, meaning that past studies report a composite of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). To identify the distinct contributions of DNA methylation modifications to axonal regeneration, we collected spinal cord tissue after sharp injury from untreated adult F3 male rats with enhanced regeneration of injured spinal axons or controls, derived from folate- or water-treated F0 lineages, respectively. Genomic DNA was profiled for genome-wide 5hmC levels, revealing 658 differentially hydroxymethylated regions (DhMRs). Genomic profiling with whole genome bisulphite sequencing disclosed regeneration-related alterations in composite 5mC + 5hmC DNA methylation levels at 2,260 differentially methylated regions (DMRs). While pathway analyses revealed that differentially hydroxymethylated and methylated genes are linked to biologically relevant axon developmental pathways, only 22 genes harbour both DhMR and DMRs. Since these differential modifications were more than 60 kilobases on average away from each other, the large majority of differential hydroxymethylated and methylated regions are unique with distinct functions in the axonal regeneration phenotype. These data highlight the importance of distinguishing independent contributions of 5mC and 5hmC levels in the central nervous system, and denote discrete roles for DNA methylation modifications in spinal cord injury and regeneration in the context of transgenerational inheritance. [ABSTRACT FROM AUTHOR]