The interplay between DNA and histone methylation: molecular mechanisms and disease implications

EMBO Reports, Journal Year: 2021, Volume and Issue: 22(5)

Published: April 12, 2021

Language: Английский

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Molecular biology of the cell

Journal of Education Health and Sport, Journal Year: 2022, Volume and Issue: 12(8), P. 730 - 926

Published: Aug. 23, 2022

The book is intended for students studying medical and biological specialties. CHAPTER I. EPIGENETICS INTRODUCTION science of epigenetics looks at the mechanisms molecular modifications histones DNA that can regulate gene activity without affecting nucleotide sequences in molecule. Recognized epigenetic regulators are methylation, post-translational histones, non-coding RNAs (nkRNAs). One most important differences between eukaryotic cells prokaryotes presence a complex nucleo-protein chromatin eukaryotes. It this form molecule stored our cells. On one hand, structural organization provides compact arrangement cell nucleus. other directly involved process regulating expression. At same time, nucleosome depicted Fig. 1 (a functional unit chromatin) considered as key component processes nucleus 8 histone proteins (octamers). consists two copies each H2A, H2B, H3 H4. chain, which includes 147 nucleotides, folds 1.65 times around octamer histones. nucleosomes arranged linear array along "beads on string". linker section connecting adjacent (transcriptionally inactive) sealed with H1-histone protein. length 30 nm. Moreover, site beginning transcription usually located inside nucleosome. Consequently, serves repressor, preventing initiation transcription. That is, total repression genes. In contrast, becomes possible result remodeling factors enable "dismantling" or otherwise alter their structure organization. Thus, (inactivation) genes begins wrapping nucleosome, liberation from (activation) involves freeing binding to unfolding by (Lorch Y., Kornberg R. D., 2017). Thanks mechanism, selective expression only those needed given time tissue possible. should be emphasized extends not transcription, but also associated molecule, such replication, mitotic division, repair double-strand breaks, maintenance telomeres. control various physiological pathological corresponding changing availability systems chromatin. scope application research methods rapidly expanding. Currently, we witnessing active introduction approaches field practical medicine aimed diagnosing treating dangerous human diseases. II. TRANSCRIPTION FACTORS For first existence was revealed basis discovery made it establish vitro purified RNA polymerase-II initiate template extract (Weil P. A. et al., 1979). Further fractionation identification general (GTF) required has identified similar rats, Drosophila, yeast substantiated assumption GTFs indeed "common" necessary transcribed polymerase highly conserved number organisms (Matsui T. 1980). We mention II because type enzyme ability synthesize mRNA. Whereas I responsible synthesis pro-rRNA, III tRNA RNAs. Meanwhile, regulation eukaryotes quite complex, since depends complexes (Burns L. G., Peterson C. L., 1997) covalent modification (Natsume-Kitatani Mamitsuka H., 2016). initiation, immediate target GTF well-defined promo zone gene. promotra eukaryotes, main elements regulatory distinguished. (bark promoter, see 2.1) attributed assembling (PIC), including TATA sequence above start (TSS ), an initiating (Inr) covering site. Promoters may include unit, initiator (Inr), both (Hampsey M., 1998). A third major element, downstream promoter element (DPE), originally described Drosophila about p.p. below TSS. DPE appears function conjunction Inr factor TFIID non-TATA promoters. According current research, cellular (main) promoters multicellular contain short nucleotides called cow (motifs) (e.g., block, lower (DPE)) recruit through common mechanism (Dreos 2021). authors report classes Inr+DPE present genome humans structurally other, different species organisms. studied box, box found 10-20% cortical Therefore, sequence, name known elements, include: BRE, MTE, TST sequences. BRE (TFIIB recognition element) motifs either (BREu) (BREd) box. TBP, demonstrate high levels conservatism range archaebacteria (Kadonaga J. T., 2012). doing so, BREu well BREd have positive negative effects activity. core (DPE) detected analysis Drosophila. MTE (motif ten element), front DPE, overrepresented "motif 10" then discovered, promoter. exhibit humans, appear recognized subunits TFIID, TAF resemble structure. turn, TCT regulates ribosomal protein humans. Although there no universal all promoters, concept nuclear defined minimum stretch sufficient accurately 2012; Haberle V., Stark A., 2018). noted results modern will constantly supplement list new components example, DNA-replicatedrelated (DRE), Ohler 1,6 7 (Danino Y. M. 2015; authors, bark transformed course evolution. Due this, modulated composition elements. Such modulation achieved emergence combinations additional level realized. To summarize facts, initiated specific position, Transcription Initiation Site (TSS), 5' end TSS embedded spanning 50 base pairs platform related (GTFs). Regulatory low basal activity, further activated, generally more distally enhancers (discussed below). Enhancers bind factors, cofactors, enhance III. CELL SIGNALING PATHWAYS organism, work regulated large signals. These signals formed organism itself, reflecting needs living (metabolic state, stages development, differentiation, reproduction), reaction external environment. implementation these encompasses biochemical lead cell's perception signal response. something receptor, turn response signal. receptor recognizes signal, interprets specificity translates into intracellular signaling molecules, cascade phosphorylation, pathways. soon (ligand) binds its – complementary transmembrane cell. Growth hormones, cytokines, neurotransmitters, extracellular matrix, etc. chemical nature ligands diverse, small molecules lipids (prostaglandins, steroid hormones), (for peptide cytokines chemokines, growth factors)., polymers sugars β-glucan zymosan) proteoglycans), nucleic acids, Binding ligand induces conformational changes translated activating cascades secondary messengers (kinases, phosphatases, GTPases, ions cAMP, cGMP, diacylglycerol, etc.). message transmitted membrane nucleus, where expression, subsequent translation targeting organelles triggered. There types receptors (transmembrane) receptors. Membrane plasma separate domain ligand, hydrophobic nature, cytoplasmic domain. Cell surface divided G-protein-bound receptors, tyrosine kinase-bound ionotropic When binds, undergo activate enzymatic domain, kinases, phosphatases adapter proteins. covalently bound capable producing transmission. Intracellular (estrogen glucocorticoid progesterone retinoic acid thyroid hormone etc.), membranes (mitochondria, endoplasmic reticulum Golgi apparatus). information received receptor) targets. All path transmission However, certain set effector proteins, enzymes substrates implement pathway (signaling cascade). Recently, however, been growing evidence themselves play extremely role signaling, theso-called scaffold ("platform proteins", adaptor proteins), coordinate assembly multicomponent complexes. Scaffold several single thereby modulating efficiency bringing closer together, direct flow cell, activating, coordinating events networks (Skovorodnikova P.A. literature, described, cover wide functions. This group three categories (Fig. 1): simple functionally dependent (adaptors), larger multi-domain designed (scaffold⁄anchoring proteins) specialized localizing proteins-components pathways (docking ( Buday Tompa P, 2010) platforms increases selectivity pathway, allows formation feedback. e ultimate ultimately allow resulting converted change (Brivanlou Darnell E., 2002). Most eventually activation repressors sequence. Eukaryotic like takes place cytoplasm. Signal multifactorial system, based nodular special cascades. none isolation. interaction inevitable complexes, when system perceives combination stimuli (hormones, pathogenic ligands), preserves accuracy (Saini N., Sarin relatively development mammals Combinations action determine decisions fate differentiation ontogenesis (Li R., Elowitz M.V., 2019; de Roo Staal F. 2020) malignancy (Dreesen O., Brivanlou A.N., 2007; Skovorodnikova Consider some medically important. IV. MOLECULAR BIOLOGY OF THE TUMOR: MECHANISMS INITIATION, PROMOTION AND PROGRESSION Tumor diseases occupy leading place, terms morbidity mortality. despite advances study genetic patterns, many unresolved questions remain. spectrum markers makes diagnose, predict course, degree malignancy, rate tumor progression therapy. occur characterized stability, they dynamic profile - appearance clones properties. heterogeneity simultaneously complicates strategy managing patients, creating prerequisites characteristics

Language: Английский

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Gut liver brain axis in diseases: the implications for therapeutic interventions

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 6, 2023

Gut-liver-brain axis is a three-way highway of information interaction system among the gastrointestinal tract, liver, and nervous systems. In past few decades, breakthrough progress has been made in gut liver brain axis, mainly through understanding its formation mechanism increasing treatment strategies. this review, we discuss various complex networks including barrier permeability, hormones, microbial metabolites, vagus nerve, neurotransmitters, immunity, toxic β-amyloid (Aβ) metabolism, epigenetic regulation gut-liver-brain axis. Some therapies containing antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), polyphenols, low FODMAP diet nanotechnology application regulate Besides, some special treatments targeting gut-liver include farnesoid X receptor (FXR) agonists, takeda G protein-coupled 5 (TGR5) glucagon-like peptide-1 (GLP-1) antagonists fibroblast growth factor 19 (FGF19) analogs. Targeting gut-brain embraces cognitive behavioral therapy (CBT), antidepressants tryptophan metabolism-related therapies. liver-brain contains Aβ future, better interactions will promote development novel preventative strategies discovery precise therapeutic targets multiple diseases.

Language: Английский

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Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 30, 2023

Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis poorly understood. The heritability estimate of MDD 30-40%, suggesting genetics alone do not account for most the risk major depression. Another factor known to associate with involves environmental stressors such as childhood adversity recent life stress. Recent studies have emerged show biological impact factors in other stress-related disorders mediated by variety epigenetic modifications. These modification alterations contribute abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission neuroglia dysfunction, which are involved pathophysiology MDD. Furthermore, marks been associated diagnosis treatment evaluation modifications holds promise further understanding heterogeneous etiology complex phenotypes MDD, may identify new therapeutic targets. Here, we review preclinical clinical findings, including DNA methylation, histone modification, noncoding RNA, RNA chromatin remodeling In addition, elaborate on contribution these mechanisms pathological trait variability depression discuss how can be exploited purposes.

Language: Английский

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Curcumin: An epigenetic regulator and its application in cancer

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 156, P. 113956 - 113956

Published: Nov. 2, 2022

Language: Английский

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Lactylation: the novel histone modification influence on gene expression, protein function, and disease

Clinical Epigenetics, Journal Year: 2024, Volume and Issue: 16(1)

Published: May 29, 2024

Abstract Lactic acid, traditionally considered as a metabolic waste product arising from glycolysis, has undergone resurgence in scientific interest since the discovery of Warburg effect tumor cells. Numerous studies have proved that lactic acid could promote angiogenesis and impair function immune cells within microenvironments. Nevertheless, precise molecular mechanisms governing these biological functions remain inadequately understood. Recently, been found to induce posttranslational modification, lactylation, may offer insight into acid's non-metabolic functions. Notably, modification proteins by lactylation emerged crucial mechanism which lactate regulates cellular processes. This article provides an overview acidification, outlines potential “writers” “erasers” responsible for protein presents patterns across different organisms, discusses diverse physiological roles lactylation. Besides, highlights latest research progress concerning regulatory pathological processes underscores its significance future investigations.

Language: Английский

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Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Epigenetic remodelling in human hepatocellular carcinoma

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: March 24, 2022

Abstract Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, being sixth commonly diagnosed cancer and fourth leading cause of cancer-related death. As other heterogeneous solid tumours, HCC results from a unique synergistic combination genetic alterations mixed with epigenetic modifications. In patterns frequencies somatic variations change depending on nearby chromatin. On hand, often induce genomic instability prone to mutations. Epigenetics refers heritable states gene expression without alteration DNA sequence itself and, unlike changes, modifications are reversible affect more extensively than changes. Thus, studies regulation involved molecular machinery greatly contributing understanding mechanisms that underline onset heterogeneity. Moreover, this knowledge may help identify biomarkers for diagnosis prognosis, as well future new targets efficacious therapeutic approaches. comprehensive review we will discuss state-of-the-art about landscape in hepatocarcinogenesis, including evidence diagnostic prognostic role non-coding RNAs, occurring at chromatin level, their era precision medicine. Apart better-known risk factors predispose development HCC, characterization remodelling occurs during hepatocarcinogenesis could open way identification personalized biomarkers. It also enable accurate stratification patients, discovery efficient

Language: Английский

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Structural and functional specificity of H3K36 methylation

Epigenetics & Chromatin, Journal Year: 2022, Volume and Issue: 15(1)

Published: May 18, 2022

The methylation of histone H3 at lysine 36 (H3K36me) is essential for maintaining genomic stability. Indeed, this mark proper transcription, recombination, and DNA damage response. Loss- gain-of-function mutations in H3K36 methyltransferases are closely linked to human developmental disorders various cancers. Structural analyses suggest that nucleosomal components such as the linker a hydrophobic patch constituted by H2A likely determinants addition tail, which encompasses catalytic SET domain. Interaction with nucleosome collaborates regulation their auto-inhibitory changes fine-tunes precision H3K36me mediating dimethylation NSD2 NSD3 well trimethylation Set2/SETD2. identification specific structural features cis-acting factors bind different forms H3K36me, particularly di-(H3K36me2) tri-(H3K36me3) methylated H3K36, have highlighted intricacy functional significance. Here, we consolidate these findings offer insight H3K36me2 H3K36me3 conversion. We also discuss mechanisms underlie cooperation between other chromatin modifications (in particular, H3K27me3, acetylation, N

Language: Английский

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FOXF2 expression triggered by endocrine therapy orchestrates therapeutic resistance through reorganization of chromatin architecture in breast cancer

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217463 - 217463

Published: Jan. 1, 2025

Language: Английский

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