Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Май 22, 2023

Abstract Over decades, researchers have focused on the epigenetic control of DNA-templated processes. Histone modification, DNA methylation, chromatin remodeling, RNA and noncoding RNAs modulate many biological processes that are crucial to development cancers. Dysregulation epigenome drives aberrant transcriptional programs. A growing body evidence suggests mechanisms modification dysregulated in human cancers might be excellent targets for tumor treatment. Epigenetics has also been shown influence immunogenicity immune cells involved antitumor responses. Thus, application therapy cancer immunotherapy their combinations may important implications Here, we present an up-to-date thorough description how modifications cell responses microenvironment (TME) epigenetics internally modify TME. Additionally, highlight therapeutic potential targeting regulators immunotherapy. Harnessing complex interplay between immunology develop therapeutics combine thereof is challenging but could yield significant benefits. The purpose this review assist understanding impact TME, so better immunotherapies can developed.

Язык: Английский

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Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation

Nature Genetics, Год журнала: 2022, Номер 54(12), С. 1895 - 1906

Опубликована: Дек. 1, 2022

Cytosine methylation efficiently silences CpG-rich regulatory regions of genes and repeats in mammalian genomes. To what extent this entails direct inhibition transcription factor (TF) binding versus indirect via recruitment methyl-CpG-binding domain (MBD) proteins is unclear. Here we show that combinatorial genetic deletions all four with functional MBDs mouse embryonic stem cells, derived neurons or a human cell line do not reactivate methylated promoters. These do, however, become activated by methylation-restricted TFs if DNA removed. We identify several causal neurons, including ONECUT1, which sensitive only at motif variant. Rampantly upregulated retrotransposons methylation-free feature CRE motif, activates them the absence methylation-sensitive CREB1. Our study reveals vivo argues inhibition, rather than repression tested MBD proteins, prevailing mechanism methylation-mediated repeats.

Язык: Английский

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Methylation across the central dogma in health and diseases: new therapeutic strategies

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Авг. 24, 2023

The proper transfer of genetic information from DNA to RNA protein is essential for cell-fate control, development, and health. Methylation DNA, RNAs, histones, non-histone proteins a reversible post-synthesis modification that finetunes gene expression function in diverse physiological processes. Aberrant methylation caused by mutations or environmental stimuli promotes various diseases accelerates aging, necessitating the development therapies correct disease-driver imbalance. In this Review, we summarize operating system across central dogma, which includes writers, erasers, readers, reader-independent outputs. We then discuss how dysregulation contributes neurological disorders, cancer, aging. Current small-molecule compounds target modifiers show modest success certain cancers. methylome-wide action lack specificity lead undesirable biological effects cytotoxicity, limiting their therapeutic application, especially with monogenic cause different directions changes. Emerging tools capable site-specific manipulation hold great promise solve dilemma. With refinement delivery vehicles, these new are well positioned advance basic research clinical translation field.

Язык: Английский

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Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage

Neuropsychiatric Disease and Treatment, Год журнала: 2022, Номер Volume 18, С. 2813 - 2835

Опубликована: Ноя. 1, 2022

Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 ( MECP2 ), which encodes MeCP2 protein. RTT -related disorder, along with duplication (MDS), gain-of-function duplications of . Nearly two decades research have advanced our knowledge function health and disease. The following review will discuss its dysregulation disorders MDS. This include discussion genetic underpinnings these disorders, specifically how sporadic X-chromosome arise manifest specific populations. We then current diagnostic guidelines clinical manifestations Next, we delve into biology, describing dual landscapes methylated DNA reader across neuronal genome as well transcriptional modulator. Following this, outline common genotype–phenotype correlations both diseases, particular focus on associated relatively mild disease RTT. also summarize modeling resulting molecular, synaptic, behavioral phenotypes Finally, list several therapeutics development pipeline for MDS available evidence their safety efficacy. Keywords: epigenetics, methylation, modeling,

Язык: Английский

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Mutation and selection processes regulating short tandem repeats give rise to genetic and phenotypic diversity across species

Journal of Evolutionary Biology, Год журнала: 2022, Номер 36(2), С. 321 - 336

Опубликована: Окт. 26, 2022

Short tandem repeats (STRs) are units of 1-6 bp that repeat in a fashion DNA. Along with single nucleotide polymorphisms and large structural variations, they among the major genomic variants underlying genetic, likely phenotypic, divergence. STRs experience mutation rates orders magnitude higher than other well-studied genotypic variants. Frequent copy number changes result wide range alleles, provide unique opportunities for modulating complex phenotypes through variation length. While classical studies have identified key roles individual STR loci, advent improved sequencing technology, high-quality genome assemblies diverse species, bioinformatics methods genome-wide analysis now enable more systematic study across evolutionary ranges. In this review, we explore selection processes affect evolution, how these give rise to varying patterns both within species. Finally, review recent examples functional adaptive linked STRs.

Язык: Английский

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Epigenetic marks or not? The discovery of novel DNA modifications in eukaryotes

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(4), С. 106791 - 106791

Опубликована: Фев. 23, 2024

Язык: Английский

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Rett Syndrome and the Role of MECP2: Signaling to Clinical Trials

Brain Sciences, Год журнала: 2024, Номер 14(2), С. 120 - 120

Опубликована: Янв. 24, 2024

Rett syndrome (RTT) is a neurological disorder that mostly affects females, with frequency of 1 in 10,000 to 20,000 live birth cases. Symptoms include stereotyped hand movements; impaired learning, language, and communication skills; sudden loss speech; reduced lifespan; retarded growth; disturbance sleep breathing; seizures; autism; gait apraxia. Pneumonia the most common cause death for patients syndrome, survival rate 77.8% at 25 years age. Survival into fifth decade typical leading cardiorespiratory compromise. progression has multiple stages; however, phenotypes are associated nervous system brain. In total, 95% cases due mutations MECP2 gene, an X-linked gene encodes methyl CpG binding protein, regulator expression. this review, we summarize recent developments field therapeutics targeting MECP2.

Язык: Английский

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Epigenetics in Ecology, Evolution, and Conservation

Frontiers in Ecology and Evolution, Год журнала: 2022, Номер 10

Опубликована: Апрель 8, 2022

Epigenetic variation is often characterized by modifications to DNA that do not alter the underlying nucleotide sequence, but can influence behavior, morphology, and physiological phenotypes affecting gene expression protein synthesis. In this review, we consider how emerging field of ecological epigenetics (eco-epi) aims use epigenetic explain ecologically relevant phenotypic predict evolutionary trajectories are important in conservation. Here, focus on data have contributed our understanding wild populations, including plants, animals, fungi. First, identified published eco-epi literature found there was limited taxonomic ecosystem coverage that, necessity available technology, these studies most focused summarized epigenome rather than locus- or nucleotide-level characteristics. We also while many adaptation heritability epigenome, has thematically expanded into topics such as disease ecology epigenome-based ageing individuals. second part synthesis, discuss key insights emerged from broadly preview path toward integration ecology. Specifically, suggest moving differences whole-epigenome incorporate several facets characterization ( e.g. , methylation, chromatin structure). Finally, incorporation behavior stress will be critical process fully integrating ecology, conservation, biology.

Язык: Английский

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State‐of‐the‐art therapies for Rett syndrome

Developmental Medicine & Child Neurology, Год журнала: 2022, Номер 65(2), С. 162 - 170

Опубликована: Сен. 3, 2022

Rett syndrome (RTT) is an X‐linked neurogenetic disorder caused by mutations of the MECP2 (methyl‐CpG‐binding protein 2) gene. Over two decades work established MeCP2 as a with pivotal roles in regulation epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given genetic aetiology RTT proof concept its reversal mouse model, considerable efforts have been made to design therapeutic approaches re‐express MeCP2. By being at forefront development innovative gene therapies, research on paramount importance for treatment monogenic neurological diseases. Here we discuss recent advances challenges promising strategies including replacement gene/RNA editing strategies, reactivation silenced X chromosome. What this paper adds Recent shed light promises therapy new vectors designed control levels expression. New developments DNA/RNA or chromosome open possibility native locus endogenous levels. Current still face limitations transduction efficiency future needed improve brain delivery.

Язык: Английский

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Choreography of lamina‐associated domains: structure meets dynamics

FEBS Letters, Год журнала: 2023, Номер 597(22), С. 2806 - 2822

Опубликована: Ноя. 1, 2023

Lamina‐associated domains are large regions of heterochromatin positioned at the nuclear periphery. These have been implicated in gene repression, especially context development. In mammals, LAD organization is dependent on lamins, inner membrane proteins, and chromatin state. addition, readers modifier proteins this organization, potentially serving as molecular tethers that interact with both envelope chromatin. More recent studies focused teasing apart rules govern dynamic how turn, relates to regulation overall 3D genome organization. This review highlights mammalian cells uncovering factors instruct choreography re‐organization, dynamics lamina, including interphase through mitotic exit, when re‐established, well intra‐LAD subdomain variations.

Язык: Английский

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