CNV biology in neurodevelopmental disorders

Current Opinion in Neurobiology, Journal Year: 2018, Volume and Issue: 48, P. 183 - 192

Published: Jan. 11, 2018

Copy number variants (CNVs), characterized in recent years by cutting-edge technology, add complexity to our knowledge of the human genome. CNVs contribute not only diversity but also different kinds diseases including neurodevelopmental delay, autism spectrum disorder and neuropsychiatric diseases. Interestingly, many pathogenic are shared among these Studies suggest that pathophysiology disease may be simply attributed a single driver gene within CNV multifactorial effects important. Gene expression resulting phenotypes affected epigenetic alteration chromosomal structural changes. Combined with genetics systems biology, integrative research multi-dimensional approaches using animal cell models expected further understanding pathophysiological mechanisms disorders disorders.

Language: Английский

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DNA methylation directs microRNA biogenesis in mammalian cells

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Dec. 11, 2019

Abstract MicroRNA (miRNA) biogenesis initiates co-transcriptionally, but how the Microprocessor machinery pinpoints locations of short precursor miRNA sequences within long flanking regions transcript is not known. Here we show that depends on DNA methylation. When coding sequence are highly methylated, miRNAs more expressed, have greater conservation, and likely to drive cancer-related phenotypes than encoded by unmethylated loci. We removal methylation from loci leads their downregulation. Further, found MeCP2 binding methylated halts RNA polymerase II elongation, leading enhanced processing primary Drosha. Taken together, our data reveal directly affects biogenesis.

Language: Английский

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Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: July 18, 2019

Abstract DNA methylation contributes to the maintenance of genomic integrity in somatic cells, part through silencing transposable elements. In this study, we use CRISPR-Cas9 technology delete DNMT1 , methyltransferase key for maintenance, human neural progenitor cells (hNPCs). We observe that inactivation hNPCs results viable, proliferating despite a global loss CpG-methylation. demethylation leads specific transcriptional activation and chromatin remodeling evolutionarily young, hominoid-specific LINE-1 elements (L1s), while older L1s other classes remain silent. The activated act as alternative promoters many protein-coding genes involved neuronal functions, revealing L1-based network controlled by influences genes. Our provide mechanistic insight into role well further implicating brain development disease.

Language: Английский

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The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder

Molecular and Cellular Neuroscience, Journal Year: 2018, Volume and Issue: 88, P. 300 - 307

Published: March 3, 2018

Language: Английский

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Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

Human Molecular Genetics, Journal Year: 2019, Volume and Issue: 28(13), P. 2201 - 2211

Published: March 7, 2019

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting role for developmentally moderated regulatory genomic variation the molecular aetiology ASD, we quantified genome-wide patterns DNA methylation 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex cerebellum (CB)] dissected 43 ASD patients 38 non-psychiatric control donors. We identified widespread differences associated with idiopathic (iASD), consistent signals both cortical that were distinct to those observed CB. Individuals carrying duplication chromosome 15q (dup15q), representing genetically defined subtype striking methylationacross discrete domain spanning an imprinted gene cluster within duplicated region. In addition dramatic cis-effects dup15q carriers, convergent methylomic signatures iASD dup15q, reflecting findings previous expression H3K27ac. Cortical co-methylation network analysis number co-methylated modules significantly are enriched annotated genes involved immune system, synaptic signalling neuronal regulation. Our study represents first systematic across multiple regions, providing novel evidence syndromic autism.

Language: Английский

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Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(1), P. 710 - 730

Published: May 17, 2021

Although the full aetiology of autism spectrum disorder (ASD) is unknown, familial and twin studies demonstrate high heritability 60-90%, indicating a predominant role genetics in development disorder. The genetic architecture ASD consists complex array rare common variants all classes variation usually acting additively to augment individual risk. relative contribution heredity persists despite selective pressures against classic autistic phenotype; phenomenon thought be explained, part, by incidence spontaneous (or de novo) mutations. Notably, environmental exposures attributed as salient risk factors for may play causal emergence deleterious novo variations, with several ASD-associated agents having significant mutagenic potential. To explore this hypothesis, review article assesses published epidemiological data evidence derived from assays mutagenicity, both vivo vitro, determine likely such augmenting liability ASD. Broadly, these were observed elicit genomic alterations through one or combination of: (1) direct interaction material; (2) impaired DNA repair; (3) oxidative damage. However, phenotype cannot determined without further analysis. comprehensive prospective birth cohorts genome sequencing essential forming causal, mechanistic account mutations that links exposure, genotypic alterations, phenotypic consequences.

Language: Английский

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Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Genome Medicine, Journal Year: 2020, Volume and Issue: 12(1)

Published: Oct. 14, 2020

Autism spectrum disorder (ASD) is a neurodevelopmental with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic environmental factors during early development influence future health outcomes.

Language: Английский

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Autism Spectrum Disorder from the Womb to Adulthood: Suggestions for a Paradigm Shift

Journal of Personalized Medicine, Journal Year: 2021, Volume and Issue: 11(2), P. 70 - 70

Published: Jan. 25, 2021

The wide spectrum of unique needs and strengths Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With plethora information from research, common thread required to conceptualize an exhaustive pathogenetic paradigm. epidemiological clinical findings in ASD cannot be explained by traditional linear genetic model, hence need move towards more fluid conception, integrating genetics, environment, epigenetics as whole. embryo-fetal period first two years life (the so-called ‘First 1000 Days’) are crucial time window neurodevelopment. In particular, interplay vicious loop between immune activation, gut dysbiosis, mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy undermines health people throughout life. Consequently, most effective intervention expected primary prevention aimed at early control main effector molecular pathways. We will reason here on comprehensive paradigm ASD, viewed not just theoretical issue, but tool provide suggestions preventive strategies personalized, dynamic (from womb adulthood), systemic, interdisciplinary approach.

Language: Английский

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Modern Biomarkers for Autism Spectrum Disorder: Future Directions

Molecular Diagnosis & Therapy, Journal Year: 2022, Volume and Issue: 26(5), P. 483 - 495

Published: June 27, 2022

Autism spectrum disorder is an increasingly prevalent neurodevelopmental in the world today, with estimated 2% of population being affected USA. A major complicating factor diagnosing, treating, and understanding autism that defining solely based on observation behavior. Thus, recent research has focused identifying specific biological abnormalities can provide clues to diagnosis treatment. Biomarkers are objective way identify measure for diagnostic purposes as well changes resulting from This current opinion paper discusses state various biomarkers currently development disorder. The types identified include prenatal history, genetics, neurological including neuroimaging, neurophysiologic, visual attention, metabolic mitochondrial, folate, trans-methylation, trans-sulfuration pathways, immune autoantibodies cytokine dysregulation, autonomic nervous system, nutritional. Many these have promising preliminary evidence post-natal pre-symptomatic risk assessment, confirmation diagnosis, subtyping, treatment response. However, most not undergone validation studies do investigate clinically relevant comparison groups. Although field biomarker promising, it appears early stages development.

Language: Английский

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PM2.5-induced alteration of DNA methylation and RNA-transcription are associated with inflammatory response and lung injury

The Science of The Total Environment, Journal Year: 2018, Volume and Issue: 650, P. 908 - 921

Published: Sept. 7, 2018

Language: Английский

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