Detection of a DNA Methylation Signature for the Intellectual Developmental Disorder, X-Linked, Syndromic, Armfield Type

A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in FAM50A. Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in FAM50A. This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding of the associated molecular mechanisms, and further enhances our ability to diagnose patients with rare disorders.

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Diet quality associated peripheral blood DNA methylation signatures

Proceedings of The Nutrition Society ◽

10.1017/s0029665120000415 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Jiantao Ma ◽

Casey Rebholz ◽

Kim Braun ◽

Lindsay Reynolds ◽

Stella Aslibekyan ◽

...

Keyword(s):

Dna Methylation ◽

Diet Quality ◽

Peripheral Blood ◽

Molecular Mechanisms ◽

Healthy Eating Index ◽

European Ancestry ◽

P Value ◽

Primary Analysis ◽

Habitual Diet ◽

Methylation Patterns

AbstractLeukocyte DNA methylation patterns associated with habitual diet may reveal molecular mechanisms involved in the pathogenesis of diet-related chronic diseases and highlight targets for prevention and treatment. We aimed to examine peripheral blood derived leukocyte DNA methylation signatures associated with diet quality. We meta-analyzed epigenome-wide associations between diet quality and DNA methylation levels at over 400,000 cytosine-guanine dinucleotides (CpGs). We conducted analysis primarily in 6,662 European ancestry (EA) participants and secondarily in a group additionally including 3,062 participants of non-European ancestry from five population-based cohort studies. DNA methylation profiles were measured in whole blood, CD4 + T-cells, or CD14 + monocytes. We used food frequency questionnaires to assess habitual intake and constructed two diet quality scores: the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI). Our primary analysis identified 32 diet-associated CpGs, 12 CpGs for MDS and 24 CpGs for AHEI (at FDR < 0.05, corresponding p-values = 1.2×10-6 and 3.1×10-6, respectively) in EA participants. Four of these CpGs were associated with both MDS and AHEI. In addition, Mendelian randomization analysis indicated that seven diet-associated CpGs were causally linked to at least one of the CVD risk factors. For example, hypermethylation of cg11250194 (FADS2), which was associated with higher diet quality scores, was also associated with lower fasting triglycerides concentrations (p-value = 1.5×10-14) and higher high-density lipoprotein cholesterol concentrations (p-value = 1.7×10-8). Transethnic meta-analysis identified nine additional CpGs associated with diet quality (either MDS or AHEI) at FDR < 0.05. Overall quality of habitual diet was associated with differential peripheral leukocyte DNA methylation levels of 32 CpGs in EA participants. The diet-associated CpGs may serve as biomarkers and targets for preventive measures in CVD health. Future studies are warranted to examine diet-associated DNA methylation patterns in larger, ethnically diverse study samples.

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Cation Lipid-Assisted PEG6-PLGA Polymer Nanoparticles Encapsulated Knocking Down Long ncRNAs Reverse Non-Coding RNA of Xist Through the Support Vector Machine Model to Regulate the Molecular Mechanisms of Gastric Cancer Cell Apoptosis

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3107 ◽

2021 ◽

Vol 17 (7) ◽

pp. 1305-1319

Author(s):

Zhengwang Sun ◽

Zirui He ◽

Rujiao Liu ◽

Zhe Zhang

Keyword(s):

Gastric Cancer ◽

Support Vector Machine ◽

Molecular Mechanisms ◽

Drug Carrier ◽

Differential Expression Analysis ◽

Gene Set Enrichment Analysis ◽

Support Vector ◽

Machine Model ◽

Knock Out ◽

Training Support

Gastric adenocarcinoma (GAC) is one kind of gastric cancer with a high incidence rate and mortality. It is essential to study the etiology of GAC and provide theoretical guidance for the prevention and treatment of GAC. Bioinformatics was used via differential expression analysis, weighted gene co-expression network analysis, gene set enrichment analysis, and a training support vector machine (SVM) model to construct a TSIX/mir-320a/Rad51 network as the research index of GAC disease. On the basis of CRISPR/Cas9 gene editing technology, the present study utilizes the Cation lipid-assisted PEG-6-PLGA polymer nanoparticle (CLAN) drug carrier system to prepare the target knock-out TSIX drug with CRISPR/CaS9 nucleic acid. Knocking down lncRNA TSIX restored the suppression role of miR-320a on Rad51 and inhibited the Rad51 expression. Simultaneously, this ceRNA network activated the ATF6 signaling pathway after endoplasmic reticulum stress to promote GAC cells’ apoptosis and inhibit the disease. TSIX/miR-320a/Rad51 network may be a potential biological target of GAC disease and provides a new strategy for treating GAC disease.

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Pathway-based Biomarkers for Breast Cancer in Proteomics

Cancer Informatics ◽

10.4137/cin.s14069 ◽

2014 ◽

Vol 13s5 ◽

pp. CIN.S14069 ◽

Cited By ~ 1

Author(s):

Fan Zhang ◽

Youping Deng ◽

Mu Wang ◽

Li Cui ◽

Renee Drabier

Keyword(s):

Breast Cancer ◽

Pathway Analysis ◽

Molecular Mechanisms ◽

Biomarker Discovery ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Support Vector ◽

Machine Model ◽

Gene Set ◽

Cancer Proteomics

Genes do not function alone but through complex biological pathways. Pathway-based biomarkers may be a reliable diagnostic tool for early detection of breast cancer due to the fact that breast cancer is not a single homogeneous disease. We applied Integrated Pathway Analysis Database (IPAD) and Gene Set Enrichment Analysis (GSEA) approaches to the study of pathway-based biomarker discovery problem in breast cancer proteomics. Our strategy for identifying and analyzing pathway-based biomarkers are threefold. Firstly, we performed pathway analysis with IPAD to build the gene set database. Secondly, we ran GSEA to identify 16 pathway-based biomarkers. Lastly, we built a Support Vector Machine model with three-way data split and fivefold cross-validation to validate the biomarkers. The approach-unraveling the intricate pathways, networks, and functional contexts in which genes or proteins function-is essential to the understanding molecular mechanisms of pathway-based biomarkers in breast cancer.

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Neurodevelopmental disorder in dsm-5 from manual to clinical practice

International Journal of Growth and Development ◽

10.25081/ijgd.2017.v1i1.14 ◽

2017 ◽

Vol 1 (1) ◽

pp. 13

Author(s):

Turki Homod Albatti

Keyword(s):

Autism Spectrum Disorder ◽

Attention Deficit Hyperactivity Disorder ◽

Intellectual Disability ◽

Attention Deficit ◽

Neurodevelopmental Disorders ◽

Developmental Disorder ◽

Autism Spectrum ◽

Hyperactivity Disorder ◽

Dsm 5 ◽

Intellectual Developmental Disorder

The new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) has a number of changes to what used to be disorders first diagnosed in childhood or infancy. This lecture outlines some of the major changes to these conditions. According to the American Psychiatric Association (APA), the publisher of the DSM-5, this chapter from the DSM-IV has been superseded by a new chapter entitled, ‘Neurodevelopmental Disorders’ The new chapter includes intellectual disability (Intellectual Developmental Disorder), communication disorders, autism spectrum disorder, attention deficit hyperactivity disorder, Specific learning disorder and motor disorders. The Neurodevelopmental Disorders section replaces the outmoded term mental retardation with intellectual disability (intellectual developmental disorder) and defines levels of severity based on adaptive functioning and not IQ scores. Attention-deficit hyperactivity disorder (ADHD) is newly placed in the Neurodevelopmental Disorders section in DSM-5, whereas it was classified with disruptive behavior disorders in DSMIV. The biggest change in the Neurodevelopmental Disorders section in DSM-5 is the creation of a new category, Autism Spectrum Disorder, along with the elimination of the DSMIV diagnostic category Pervasive Developmental Disorder and its subgroupings. ASD is characterized by deficits in two core domains instead of three as in DSMIV. other changes will be explain.

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Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease

Human Molecular Genetics ◽

10.1093/hmg/ddab257 ◽

2021 ◽

Author(s):

Wen-Qiang Zheng ◽

Signe Vandal Pedersen ◽

Kyle Thompson ◽

Emanuele Bellacchio ◽

Courtney E French ◽

...

Keyword(s):

Molecular Mechanisms ◽

Clinical Phenotype ◽

Homology Modelling ◽

Mitochondrial Diseases ◽

Trna Synthetase ◽

Unrelated Patient ◽

Mitochondrial Translation ◽

Respiratory Chain Enzyme ◽

Functional Studies ◽

Pathogenic Variants

Abstract TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. Additionally, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modelling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

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Etiology and Pathogenesis of Hemifacial Microsomia

Journal of Dental Research ◽

10.1177/0022034518795609 ◽

2018 ◽

Vol 97 (12) ◽

pp. 1297-1305 ◽

Cited By ~ 11

Author(s):

Q. Chen ◽

Y. Zhao ◽

G. Shen ◽

J. Dai

Keyword(s):

Molecular Mechanisms ◽

Maternal Diabetes ◽

Abnormal Development ◽

Future Research ◽

Hemifacial Microsomia ◽

Vascular Abnormality ◽

Intrinsic Factors ◽

Functional Studies ◽

Pathogenic Variants ◽

Genetic Interventions

Hemifacial microsomia (HFM) is a common congenital malformation of the craniofacial region. There are 3 possible pathogenic models of HFM—vascular abnormality and hemorrhage in the craniofacial region, damage to Meckel’s cartilage, and the abnormal development of cranial neural crest cells—and the most plausible hypothesis is the vascular abnormality and hemorrhage model. These 3 models are interrelated, and none of them is completely concordant with all the variable manifestations of HFM. External environmental factors (e.g., thalidomide, triazene, retinoic acid, and vasoactive medications), maternal intrinsic factors (e.g., maternal diabetes), and genetic factors (e.g., the recently reported mutations in OTX2, PLCD3, and MYT1) may lead to HFM through ≥1 of these pathogenic processes. Whole genome sequencing to identify additional pathogenic variants, biological functional studies to understand the exact molecular mechanisms, and additional animal model and clinical studies with large stratified samples to elucidate the pathogenesis of HFM will be necessary. Small-molecule drugs, as well as CRISPR/CAS9-based genetic interventions, for the prevention and treatment of HFM may also be a future research hotspot.

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Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease

10.1101/468470 ◽

2018 ◽

Author(s):

Mikko Konki ◽

Maia Malonzo ◽

Ida K. Karlsson ◽

Noora Lindgren ◽

Bishwa Ghimire ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Peripheral Blood ◽

Molecular Mechanisms ◽

Bisulfite Sequencing ◽

Disease Risk ◽

Gene Array ◽

Discordant Twin

ABSTRACTAlzheimer’s disease (AD) results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. As life style factors largely modulate the disease risk, we hypothesised that the disease associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. Reduced Representation Bisulfite Sequencing, single cell RNA-sequencing and gene array data were utilised to examine DNA methylation signatures and associated gene expression changes in blood and hippocampus, and targeted bisulfite sequencing in cross cohort validation. Our results reveal that discordant twin pairs have disease associated differences in their peripheral blood epigenomes. A subset of affected genes, e.g.ADARB2contain differentially methylated sites also in anterior hippocampus. The DNA methylation differences seem to influence gene expression in brain rather than in blood cells. The affected genes are associated with neuronal functions and pathologies. These DNA methylation signatures are valuable disease marker candidates and may provide insights into the molecular mechanisms of pathogenesis.

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Predicting Ink Transfer Rate of 3D Additive Printing Using EGBO Optimized Least Squares Support Vector Machine Model

Mathematical Problems in Engineering ◽

10.1155/2020/8642430 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Shengpu Li ◽

Yize Sun

Keyword(s):

Support Vector Machine ◽

Prediction Model ◽

Least Squares ◽

Transfer Rate ◽

Coefficient Of Determination ◽

Percentage Error ◽

Support Vector ◽

Experimental Sample ◽

Machine Model ◽

Ink Transfer

Ink transfer rate (ITR) is a reference index to measure the quality of 3D additive printing. In this study, an ink transfer rate prediction model is proposed by applying the least squares support vector machine (LSSVM). In addition, enhanced garden balsam optimization (EGBO) is used for selection and optimization of hyperparameters that are embedded in the LSSVM model. 102 sets of experimental sample data have been collected from the production line to train and test the hybrid prediction model. Experimental results show that the coefficient of determination (R2) for the introduced model is equal to 0.8476, the root-mean-square error (RMSE) is 6.6 × 10 (−3), and the mean absolute percentage error (MAPE) is 1.6502 × 10 (−3) for the ink transfer rate of 3D additive printing.

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DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽

10.3390/biom11020142 ◽

2021 ◽

Vol 11 (2) ◽

pp. 142

Author(s):

Mariella Cuomo ◽

Luca Borrelli ◽

Rosa Della Monica ◽

Lorena Coretti ◽

Giulia De Riso ◽

...

Keyword(s):

Dna Methylation ◽

Molecular Mechanisms ◽

The Past ◽

Targeted Analysis ◽

Lack Of Information ◽

High Resolution Power ◽

Resolution Level ◽

Health And Disease ◽

High Doses ◽

The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

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Copy number-dependent DNA methylation of the Pyricularia oryzae MAGGY retrotransposon is triggered by DNA damage

Communications Biology ◽

10.1038/s42003-021-01836-5 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Ba Van Vu ◽

Quyet Nguyen ◽

Yuki Kondo-Takeoka ◽

Toshiki Murata ◽

Naoki Kadotani ◽

...

Keyword(s):

Dna Methylation ◽

Copy Number ◽

Rna Silencing ◽

Molecular Mechanisms ◽

De Novo ◽

Pyricularia Oryzae ◽

Transcriptional Gene Silencing ◽

Physical Interaction ◽

Uncharacterized Protein ◽

Form Complex

AbstractTransposable elements are common targets for transcriptional and post-transcriptional gene silencing in eukaryotic genomes. However, the molecular mechanisms responsible for sensing such repeated sequences in the genome remain largely unknown. Here, we show that machinery of homologous recombination (HR) and RNA silencing play cooperative roles in copy number-dependent de novo DNA methylation of the retrotransposon MAGGY in the fungusPyricularia oryzae. Genetic and physical interaction studies revealed thatRecAdomain-containing proteins, includingP. oryzaehomologs ofRad51, Rad55, andRad57, together with an uncharacterized protein, Ddnm1, form complex(es) and mediate either the overall level or the copy number-dependence of de novo MAGGY DNA methylation, likely in conjunction with DNA repair. Interestingly,P. oryzaemutants of specific RNA silencing components (MoDCL1andMoAGO2)were impaired in copy number-dependence of MAGGY methylation. Co-immunoprecipitation of MoAGO2 and HR components suggested a physical interaction between the HR and RNA silencing machinery in the process.

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