Potential therapeutic relevance of CRISPR/Cas9 guided Epigenetic Regulations for Neuropsychiatric Disorders

2021 ◽  
Vol 21 ◽  
Author(s):  
Desh Deepak Singh ◽  
Ravi Verma ◽  
Piyush Parimoo ◽  
Ashish Sahu ◽  
Vikram Kumar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanism ◽  
Brain Function ◽  
Normal Development ◽  
Neuropsychiatric Disorders ◽  
Regulatory Mechanisms ◽  
Epigenetic Factors ◽  
Non Coding Rna ◽  
Epigenetic Regulations ◽  
Function Activity

Brain function activity is regulated by several mechanisms of genetic and epigenetic factors such as histone modelling, DNA methylation, and non-coding RNA. Alteration in these regulatory mechanisms affect normal development of neurons that causes Neuropsychiatric Disorders (ND). However, it is required to analyse the functional significance of neuropsychiatric disorders associated to molecular mechanism to therapeutic advances in early diagnosis and treatment of the patients. The CRISPR/Cas 9 (Clustered Regularly Interspaced Short Palindromic Repeats) genome editing tools have revolutionized multiple genome and epigenome manipulation targets same time. This review discussed the possibilities about using CRISPR/Cas 9 tools during molecular mechanism in the ND, to obtain therapeutic approach of this amazing technique to overcome ND that generates because of genetics and epigenetic abnormalities.

DNA methyltransferase inhibitors modulate histone methylation: epigenetic crosstalk between H3K4me3 and DNA methylation during sperm differentiation

Zygote ◽  
2021 ◽  
pp. 1-6
Author(s):  
Liliana Burlibaşa ◽  
Alina-Teodora Nicu ◽  
Carmen Domnariu
Keyword(s):  
Dna Methylation ◽  
Histone Methylation ◽  
Dna Methyltransferase ◽  
Integrated Approach ◽  
Regulatory Mechanisms ◽  
Temporal Expression ◽  
Dna Methyltransferase Inhibitors ◽  
Expression Of Genes ◽  
Species Survival ◽  
Advanced Stages

Summary The process of cytodifferentiation in spermatogenesis is governed by a unique genetic and molecular programme. In this context, accurate ‘tuning’ of the regulatory mechanisms involved in germ cells differentiation is required, as any error could have dramatic consequences on species survival and maintenance. To study the processes that govern the spatial–temporal expression of genes, as well as analyse transmission of epigenetic information to descendants, an integrated approach of genetics, biochemistry and cytology data is necessary. As information in the literature on interplay between DNA methylation and histone H3 lysine 4 trimethylation (H3K4me3) in the advanced stages of murine spermatogenesis is still scarce, we investigated the effect of a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, at the cytological level using immunocytochemistry methodology. Our results revealed a particular distribution of H3K4me3 during sperm cell differentiation and highlighted an important role for regulation of DNA methylation in controlling histone methylation and chromatin remodelling during spermatogenesis.

scholarly journals Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Suleyman Vural ◽  
Alida Palmisano ◽  
William C. Reinhold ◽  
Yves Pommier ◽  
Beverly A. Teicher ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antitumor Agents ◽  
Cancer Cell Lines ◽  
Chemotherapeutic Agents ◽  
Epigenetic Factors ◽  
Expression Of Genes ◽  
Genes Encoding

Abstract Background Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents. Results We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta-values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epigenome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxygenases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes affecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlapping effects of each epigenetic factor on methylation of specific targets and the importance of such influences in tumor response to individual agents require further investigation. Conclusions Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may affect response to therapeutic agents. Our findings suggest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly affect response to chemotherapy.

scholarly journals DNA methylation as predictive marker of response to immunotherapy?

2021 ◽  
Author(s):  
Gerwin Heller
Keyword(s):  
Dna Methylation ◽  
Cancer Treatment ◽  
Treatment Efficacy ◽  
Predictive Marker ◽  
Short Review ◽  
Predictive Markers ◽  
Epigenetic Factors

SummaryImmunotherapy is one of the major breakthroughs in cancer treatment. However, many patients do not benefit from this type of therapy. Thus, there is an urgent need for a strategy to predict treatment efficacy before start of therapy. The role of certain genetic and epigenetic factors as potential predictive markers for response to immunotherapy is discussed in this short review.

scholarly journals PGC7 suppresses TET3 for protecting DNA methylation

2013 ◽  
Vol 42 (5) ◽  
pp. 2893-2905 ◽  
Author(s):  
Chunjing Bian ◽  
Xiaochun Yu
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanism ◽  
Biological Process ◽  
Cpg Islands ◽  
Binding Motifs ◽  
Genome Wide Analysis ◽  
Dna Motif ◽  
Genome Wide

Abstract Ten-eleven translocation (TET) family enzymes convert 5-methylcytosine to 5-hydroxylmethylcytosine. However, the molecular mechanism that regulates this biological process is not clear. Here, we show the evidence that PGC7 (also known as Dppa3 or Stella) interacts with TET2 and TET3 both in vitro and in vivo to suppress the enzymatic activity of TET2 and TET3. Moreover, lacking PGC7 induces the loss of DNA methylation at imprinting loci. Genome-wide analysis of PGC7 reveals a consensus DNA motif that is recognized by PGC7. The CpG islands surrounding the PGC7-binding motifs are hypermethylated. Taken together, our study demonstrates a molecular mechanism by which PGC7 protects DNA methylation from TET family enzyme-dependent oxidation.

scholarly journals Dicer-like proteins influence Arabidopsis root microbiota independent of RNA-directed DNA methylation

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Richa Kaushal ◽  
Li Peng ◽  
Sunil K. Singh ◽  
Mengrui Zhang ◽  
Xinlian Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Wall ◽  
Plant Defense ◽  
Root Exudates ◽  
Rrna Gene ◽  
Epigenetic Factors ◽  
Callose Deposition ◽  
Arabidopsis Root ◽  
Triple Mutation ◽  
Root Microbiota

Abstract Background Plants are naturally associated with root microbiota, which are microbial communities influential to host fitness. Thus, it is important to understand how plants control root microbiota. Epigenetic factors regulate the readouts of genetic information and consequently many essential biological processes. However, it has been elusive whether RNA-directed DNA methylation (RdDM) affects root microbiota assembly. Results By applying 16S rRNA gene sequencing, we investigated root microbiota of Arabidopsis mutants defective in the canonical RdDM pathway, including dcl234 that harbors triple mutation in the Dicer-like proteins DCL3, DCL2, and DCL4, which produce small RNAs for RdDM. Alpha diversity analysis showed reductions in microbe richness from the soil to roots, reflecting the selectivity of plants on root-associated bacteria. The dcl234 triple mutation significantly decreases the levels of Aeromonadaceae and Pseudomonadaceae, while it increases the abundance of many other bacteria families in the root microbiota. However, mutants of the other examined key players in the canonical RdDM pathway showed similar microbiota as Col-0, indicating that the DCL proteins affect root microbiota in an RdDM-independent manner. Subsequently gene analysis by shotgun sequencing of root microbiome indicated a selective pressure on microbial resistance to plant defense in the dcl234 mutant. Consistent with the altered plant-microbe interactions, dcl234 displayed altered characters, including the mRNA and sRNA transcriptomes that jointly highlighted altered cell wall organization and up-regulated defense, the decreased cellulose and callose deposition in root xylem, and the restructured profile of root exudates that supported the alterations in gene expression and cell wall modifications. Conclusion Our findings demonstrate an important role of the DCL proteins in influencing root microbiota through integrated regulation of plant defense, cell wall compositions, and root exudates. Our results also demonstrate that the canonical RdDM is dispensable for Arabidopsis root microbiota. These findings not only establish a connection between root microbiota and plant epigenetic factors but also highlight the complexity of plant regulation of root microbiota.

ADAMTS9-AS2: A functional long non-coding RNA in tumorigenesis

2021 ◽  
Vol 27 ◽  
Author(s):  
Wen Xu ◽  
Bei Wang ◽  
Yuxuan Cai ◽  
Jinlan Chen ◽  
Xing Lv ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Signaling Pathways ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Migration Inhibition ◽  
Cancer Proliferation ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Long Non Coding Rna

Background: Long non-coding RNAs (lncRNA) have been identified as novel molecular regulators in cancers. LncRNA ADAMTS9-AS2 can mediate the occurrence and development of cancer through various ways such as regulating miRNAs, activating the classical signaling pathways in cancer, and so on, which have been studied by many scholars. In this review, we summarize the molecular mechanisms of ADAMTS9-AS2 in different human cancers. Methods: Through a systematic search of PubMed, lncRNA ADAMTS9-AS2 mediated molecular mechanisms in cancer are summarized inductively. Results: ADAMTS9-AS2 aberrantly expression in different cancers is closely related to cancer proliferation, invasion, migration, inhibition of apoptosis. The involvement of ADAMTS9-AS2 in DNA methylation, mediating PI3K / Akt / mTOR signaling pathways, regulating miRNAs and proteins, and such shows its significant potential as a therapeutic cancer target. Conclusion: LncRNA ADAMTS9-AS2 can become a promising biomolecular marker and a therapeutic target for human cancer.

scholarly journals LncRNA-MALAT1-mediated Axl promotes cell invasion and migration in human neuroblastoma

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769979 ◽  
Author(s):  
Shaojie Bi ◽  
Chunyan Wang ◽  
Yixin Li ◽  
Wei Zhang ◽  
Juan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Invasion ◽  
Neuroblastoma Cells ◽  
Great Influence ◽  
Regulatory Mechanisms ◽  
Human Neuroblastoma ◽  
Invasion And Migration ◽  
Non Coding Rna ◽  
And Migration ◽  
Long Non Coding Rna

Overexpression of Axl has been noted to correlate with several human cancers. However, the regulatory mechanisms and effects of Axl in human neuroblastoma development remain unclear. Here, we explore the expression of Axl in neurobalstoma and related upstream regulatory mechanisms of invasion and migration. We found that Axl was overexpressed in metastatic neuroblastoma tissues and positively associated with long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1. Meanwhile, our data suggested that metastasis-associated lung adenocarcinoma transcript 1 upregulated Axl expression in neuroblastoma cells, resulting in cell invasion and migration. Furthermore, we found that targeting Axl by inhibitor R428 significantly suppressed the abilities of tumor cell invasion and migration. In summary, these results suggested that Axl, which is regulated by long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1, may exert great influence on invasion and migration of neuroblastoma.

scholarly journals Genetic and epigenetic associations of ANRIL with coronary artery disease and risk factors

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Bayi Xu ◽  
Zhixia Xu ◽  
Yequn Chen ◽  
Nan Lu ◽  
Zhouwu Shu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Coronary Artery Disease ◽  
Dna Methylation ◽  
Coronary Artery ◽  
Gene Dosage ◽  
Density Lipoprotein ◽  
Nucleotide Polymorphisms ◽  
Coronary Syndrome ◽  
Non Coding Rna ◽  
Artery Disease

Abstract Background Both DNA genotype and methylation of antisense non-coding RNA in the INK4 locus (ANRIL) have been robustly associated with coronary artery disease (CAD), but the interdependent mechanisms of genotype and methylation remain unclear. Methods Eighteen tag single nucleotide polymorphisms (SNPs) of ANRIL were genotyped in a matched case–control study (cases 503 and controls 503). DNA methylation of ANRIL and the INK4/ARF locus (p14ARF, p15INK4b and p16INK4a) was measured using pyrosequencing in the same set of samples (cases 100 and controls 100). Results Polymorphisms of ANRIL (rs1004638, rs1333048 and rs1333050) were significantly associated with CAD (p < 0.05). The incidence of CAD, multi-vessel disease, and modified Gensini scores demonstrated a strong, direct association with ANRIL gene dosage (p < 0.05). There was no significant association between ANRIL polymorphisms and myocardial infarction/acute coronary syndrome (MI/ACS) (p > 0.05). Methylation levels of ANRIL were similar between the two studied groups (p > 0.05), but were different in the rs1004638 genotype, with AA and AT genotype having a higher level of ANRIL methylation (pos4, p = 0.006; pos8, p = 0.019). Further Spearman analyses indicated that methylation levels of ANRIL were positively associated with systolic blood pressure (pos6, r = 0.248, p = 0.013), diastolic blood pressure (pos3, r = 0.213, p = 0.034; pos6, r = 0.220, p = 0.028), and triglyceride (pos4, r = 0.253, p = 0.013), and negatively associated with high-density lipoprotein cholesterol (pos2, r = − 0.243, p = 0.017). Additionally, we identified 12 transcription factor binding sites (TFBS) within the methylated ANRIL region, and functional annotation indicated these TFBS were associated with basal transcription. Methylation at the INK4/ARF locus was not associated with ANRIL genotype. Conclusions These results indicate that ANRIL genotype (tag SNPs rs1004638, rs1333048 and rs1333050) mainly affects coronary atherosclerosis, but not MI/ACS. There may be allele-related DNA methylation and allele-related binding of transcription factors within the ANRIL promoter.

scholarly journals Assessment of tuberous sclerosis-associated neuropsychiatric disorders using the MINI-KID tool: a pediatric cohort study

2021 ◽  
Author(s):  
Yifeng Ding ◽  
Ji Wang ◽  
Hao Zhou ◽  
Taoli Li ◽  
Shuizhen Zhou ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Normal Development ◽  
Refractory Epilepsy ◽  
Neuropsychiatric Disorders ◽  
Number Of Children ◽  
Hyperactivity Disorder ◽  
Neuropsychiatric Diseases ◽  
Rapid Control ◽  
Development Group ◽  
Neuropsychiatric Illness

Abstract Background: Tuberous sclerosis-associated neuropsychiatric disorders (TANDs) have not been studied before in China. We aimed to assess the psychiatric level of TAND using the Mini International Neuropsychiatric Interview for Children (MINI-KID) in China.Results: A total of 83.16% of patients (79/95) had at least one TAND, and 70.53% (67/95) had an intellectual disability. The MINI-KID tool diagnosed a total of 16 neuropsychiatric diseases, the most common of which were attention-deficit/hyperactivity disorder (ADHD) (51.58%, 49/95) and social anxiety disorder (41.05%, 39/95). The number of children with neuropsychiatric diseases in the TSC group was significantly greater than the number in the normal development group (p <0.0001). Epilepsy before the age of 2 years, a seizure frequency of more than once a month, and the use of more than 2 antiepileptic drugs were closely associated with the occurrence of TAND.Conclusion: The MINI-KID can be used as a standardized tool to examine the psychiatric level of TANDs in children with TSC aged 6-16 years. The rate of neuropsychiatric diseases in children with TSC reached 83.16%. Early onset of epilepsy, frequent seizures, and refractory epilepsy are risk factors for TAND. Early, reasonable, and rapid control of seizures is related to reducing the risk of neuropsychiatric illness in children with epilepsy.

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