scholarly journals Where Environment Meets Cognition: A Focus on Two Developmental Intellectual Disability Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-20 ◽  
Author(s):  
I. De Toma ◽  
L. Manubens Gil ◽  
S. Ossowski ◽  
M. Dierssen
Keyword(s):  
Gene Expression ◽  
Intellectual Disability ◽  
Fragile X ◽  
Chromatin Accessibility ◽  
Adult Brain ◽  
Epigenetic Alterations ◽  
Brain Gene Expression ◽  
Epigenetic Machinery ◽  
Context Specific ◽  
Global And Local

One of the most challenging questions in neuroscience is to dissect how learning and memory, the foundational pillars of cognition, are grounded in stable, yet plastic, gene expression states. All known epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodelling, and noncoding RNAs regulate brain gene expression, both during neurodevelopment and in the adult brain in processes related to cognition. On the other hand, alterations in the various components of the epigenetic machinery have been linked to well-known causes of intellectual disability disorders (IDDs). Two examples are Down Syndrome (DS) and Fragile X Syndrome (FXS), where global and local epigenetic alterations lead to impairments in synaptic plasticity, memory, and learning. Since epigenetic modifications are reversible, it is theoretically possible to use epigenetic drugs as cognitive enhancers for the treatment of IDDs. Epigenetic treatments act in a context specific manner, targeting different regions based on cell and state specific chromatin accessibility, facilitating the establishment of the lost balance. Here, we discuss epigenetic studies of IDDs, focusing on DS and FXS, and the use of epidrugs in combinatorial therapies for IDDs.

scholarly journals Modeling gene regulation from paired expression and chromatin accessibility data

2017 ◽  
Vol 114 (25) ◽  
pp. E4914-E4923 ◽  
Author(s):  
Zhana Duren ◽  
Xi Chen ◽  
Rui Jiang ◽  
Yong Wang ◽  
Wing Hung Wong
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Joint Modeling ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Exciting Opportunity ◽  
Transcriptional Regulatory ◽  
Dna Elements ◽  
Context Specific

The rapid increase of genome-wide datasets on gene expression, chromatin states, and transcription factor (TF) binding locations offers an exciting opportunity to interpret the information encoded in genomes and epigenomes. This task can be challenging as it requires joint modeling of context-specific activation of cis-regulatory elements (REs) and the effects on transcription of associated regulatory factors. To meet this challenge, we propose a statistical approach based on paired expression and chromatin accessibility (PECA) data across diverse cellular contexts. In our approach, we model (i) the localization to REs of chromatin regulators (CRs) based on their interaction with sequence-specific TFs, (ii) the activation of REs due to CRs that are localized to them, and (iii) the effect of TFs bound to activated REs on the transcription of target genes (TGs). The transcriptional regulatory network inferred by PECA provides a detailed view of how trans- and cis-regulatory elements work together to affect gene expression in a context-specific manner. We illustrate the feasibility of this approach by analyzing paired expression and accessibility data from the mouse Encyclopedia of DNA Elements (ENCODE) and explore various applications of the resulting model.

scholarly journals Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice

PLoS ONE ◽  
2015 ◽  
Vol 10 (11) ◽  
pp. e0142630 ◽  
Author(s):  
Monika Burns ◽  
Sureshkumar Muthupalani ◽  
Zhongming Ge ◽  
Timothy C. Wang ◽  
Vasudevan Bakthavatchalu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Helicobacter Pylori ◽  
Serum Iron ◽  
Adult Brain ◽  
Helicobacter Pylori Infection ◽  
Iron Storage ◽  
Brain Gene Expression

scholarly journals Integrating regulatory DNA sequence and gene expression to predict genome-wide chromatin accessibility across cellular contexts

2019 ◽  
Author(s):  
Surag Nair ◽  
Daniel S. Kim ◽  
Jacob Perricone ◽  
Anshul Kundaje
Keyword(s):  
Gene Expression ◽  
Dna Sequence ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Genomic Region ◽  
Regulatory Sequence ◽  
Specific Expression ◽  
Genome Wide ◽  
Context Specific ◽  
Regulatory Dna

AbstractMotivationGenome-wide profiles of chromatin accessibility and gene expression in diverse cellular contexts are critical to decipher the dynamics of transcriptional regulation. Recently, convolutional neural networks (CNNs) have been used to learn predictive cis-regulatory DNA sequence models of context-specific chromatin accessibility landscapes. However, these context-specific regulatory sequence models cannot generalize predictions across cell types.ResultsWe introduce multi-modal, residual neural network architectures that integrate cis-regulatory sequence and context-specific expression of trans-regulators to predict genome-wide chromatin accessibility profiles across cellular contexts. We show that the average accessibility of a genomic region across training contexts can be a surprisingly powerful predictor. We leverage this feature and employ novel strategies for training models to enhance genome-wide prediction of shared and context-specific chromatin accessible sites across cell types. We interpret the models to reveal insights into cis and trans regulation of chromatin dynamics across 123 diverse cellular contexts.AvailabilityThe code is available athttps://github.com/kundajelab/[email protected]

scholarly journals Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia-related genes

2018 ◽  
Author(s):  
Rafael Romero-Garcia ◽  
Jakob Seidlitz ◽  
Kirstie J Whitaker ◽  
Sarah E Morgan ◽  
Peter Fonagy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Magnetization Transfer ◽  
Gene Expression Pattern ◽  
Structural Mri ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Genomic Variation ◽  
Adult Brain ◽  
Brain Gene Expression ◽  
Histological Data

AbstractBackgroundGenetic risk is thought to drive clinical variation on a spectrum of schizophrenia-like traits but the underlying changes in brain structure that mechanistically link genomic variation to schizotypal experience and behaviour are unclear.MethodsWe assessed schizotypy using a self-reported questionnaire, and measured magnetization transfer (MT), as a putative micro-structural MRI marker of intra-cortical myelination, in 68 brain regions, in 248 healthy young people (aged 14-25 years). We used normative adult brain gene expression data, and partial least squares (PLS) analysis, to find the weighted gene expression pattern that was most co-located with the cortical map of schizotypy-related magnetization (SRM).ResultsMagnetization was significantly correlated with schizotypy in bilateral posterior cingulate cortex and precuneus (and for disorganized schizotypy also in medial prefrontal cortex; all FDR-corrected P < 0.05), which are regions of the default mode network specialized for social and memory functions. The genes most positively weighted on the whole genome expression map co-located with SRM were enriched for genes that were significantly down-regulated in two prior case-control histological studies of brain gene expression in schizophrenia. Conversely, the most negatively weighted genes were enriched for genes that were transcriptionally up-regulated in schizophrenia. Positively weighted (down-regulated) genes were enriched for neuronal, specifically inter-neuronal, affiliations and coded a network of proteins comprising a few highly interactive “hubs” such as parvalbumin and calmodulin.ConclusionsMicrostructural MRI maps of intracortical magnetization can be linked to both the behavioural traits of schizotypy and to prior histological data on dysregulated gene expression in schizophrenia.

scholarly journals Shared genetic effects on chromatin and gene expression reveal widespread enhancer priming in immune response

2017 ◽  
Author(s):  
Kaur Alasoo ◽  
Julia Rodrigues ◽  
Subhankar Mukhopadhyay ◽  
Andrew J. Knights ◽  
Alice L. Mann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Large Fraction ◽  
Chromatin Accessibility ◽  
Genetic Effects ◽  
Small Subset ◽  
Regulatory Variants ◽  
Large Numbers ◽  
Cell Type Specific ◽  
Context Specific

AbstractNoncoding regulatory variants are often highly context-specific, modulating gene expression in a small subset of possible cellular states. Although these genetic effects are likely to play important roles in disease, the molecular mechanisms underlying context-specificity are not well understood. Here, we identify shared quantitative trait loci (QTLs) for chromatin accessibility and gene expression (eQTLs) and show that a large fraction (∼60%) of eQTLs that appear following macrophage immune stimulation alter chromatin accessibility in unstimulated cells, suggesting they perturb enhancer priming. We show that such variants are likely to influence the binding of cell type specific transcription factors (TFs), such as PU.1, which then indirectly alter the binding of stimulus-specific TFs, such as NF-κB or STAT2. Our results imply that, although chromatin accessibility assays are powerful for fine mapping causal noncoding variants, detecting their downstream impact on gene expression will be challenging, requiring profiling of large numbers of stimulated cellular states and timepoints.

scholarly journals Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Teresa Romeo Luperchio ◽  
Leandros Boukas ◽  
Li Zhang ◽  
Genay Pilarowski ◽  
Jenny Jiang ◽  
...  
Keyword(s):  
Iga Deficiency ◽  
Chromatin Accessibility ◽  
Epigenetic Variation ◽  
Gene Promoters ◽  
Epigenetic Alterations ◽  
Rna Seq ◽  
Causative Gene ◽  
Epigenetic Machinery ◽  
Overlap Analysis

Although each Mendelian Disorder of the Epigenetic Machinery (MDEM) has a different causative gene, there are shared disease manifestations. We hypothesize that this phenotypic convergence is a consequence of shared epigenetic alterations. To identify such shared alterations, we interrogate chromatin (ATAC-seq) and expression (RNA-seq) states in B cells from three MDEM mouse models (Kabuki [KS] type 1 and 2 and Rubinstein-Taybi type 1 [RT1] syndromes). We develop a new approach for the overlap analysis and find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often disrupts downstream gene expression, and identify 587 loci and 264 genes with shared disruption across all three MDEMs. Subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1, but not in KS2. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

scholarly journals Integrating regulatory DNA sequence and gene expression to predict genome-wide chromatin accessibility across cellular contexts

2019 ◽  
Vol 35 (14) ◽  
pp. i108-i116 ◽  
Author(s):  
Surag Nair ◽  
Daniel S Kim ◽  
Jacob Perricone ◽  
Anshul Kundaje
Keyword(s):  
Gene Expression ◽  
Dna Sequence ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Supplementary Information ◽  
Regulatory Sequence ◽  
Specific Expression ◽  
Genome Wide ◽  
Context Specific ◽  
Regulatory Dna

Abstract Motivation Genome-wide profiles of chromatin accessibility and gene expression in diverse cellular contexts are critical to decipher the dynamics of transcriptional regulation. Recently, convolutional neural networks have been used to learn predictive cis-regulatory DNA sequence models of context-specific chromatin accessibility landscapes. However, these context-specific regulatory sequence models cannot generalize predictions across cell types. Results We introduce multi-modal, residual neural network architectures that integrate cis-regulatory sequence and context-specific expression of trans-regulators to predict genome-wide chromatin accessibility profiles across cellular contexts. We show that the average accessibility of a genomic region across training contexts can be a surprisingly powerful predictor. We leverage this feature and employ novel strategies for training models to enhance genome-wide prediction of shared and context-specific chromatin accessible sites across cell types. We interpret the models to reveal insights into cis- and trans-regulation of chromatin dynamics across 123 diverse cellular contexts. Availability and implementation The code is available at https://github.com/kundajelab/ChromDragoNN. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Allele-specific open chromatin in human iPSC neurons elucidates functional non-coding disease variants

2019 ◽  
Author(s):  
Siwei Zhang ◽  
Hanwen Zhang ◽  
Min Qiao ◽  
Yifan Zhou ◽  
Siming Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Induced Pluripotent Stem Cell ◽  
Chromatin Accessibility ◽  
Adult Brain ◽  
Open Chromatin ◽  
Brain Disorders ◽  
Functional Interpretation ◽  
Allele Specific ◽  
Induced Pluripotent

AbstractFunctional interpretation of noncoding disease variants, which likely regulate gene expression, has been challenging. Chromatin accessibility strongly influences gene expression during neurodevelopment; however, to what extent genetic variants can alter chromatin accessibility in the context of brain disorders/traits is unknown. Using human induced pluripotent stem cell (iPSC)-derived neurons as a neurodevelopmental model, we identified abundant open-chromatin regions absent in adult brain samples and thousands of genetic variants exhibiting allele-specific open-chromatin (ASoC). ASoC variants are overrepresented in brain enhancers, transcription-factor-binding sites, and quantitative-trait-loci associated with gene expression, histone modification, and DNA methylation. Notably, compared to open chromatin regions and other commonly used functional annotations, neuronal ASoC variants showed much stronger enrichments of risk variants for various brain disorders/traits. Our study provides the first snapshot of the neuronal ASoC landscape and a powerful framework for prioritizing functional disease variants.One Sentence SummaryAllele-specific open chromatin informs functional disease variants

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