scholarly journals Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk

Science ◽  
2018 ◽  
Vol 362 (6420) ◽  
pp. eaat4311 ◽  
Author(s):  
Prashanth Rajarajan ◽  
Tyler Borrman ◽  
Will Liao ◽  
Nadine Schrode ◽  
Erin Flaherty ◽  
...  
Keyword(s):  
Neural Progenitor Cells ◽  
Disease Risk ◽  
Three Dimensional ◽  
Cell Type ◽  
Contact Map ◽  
Developmentally Regulated ◽  
Risk Variants ◽  
Cell Type Specific ◽  
Spatial Genome Organization ◽  
Developmental Remodeling

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type–specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type–specific disease risk vulnerabilities in spatial genome organization.

scholarly journals Integration of functional genomics data to uncover cell type-specific pathways affected in Parkinson's disease

2021 ◽  
Author(s):  
Viola Volpato
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
Late Onset ◽  
Alpha Synuclein ◽  
Biological Information ◽  
Cell Type ◽  
Risk Variants ◽  
Cell Type Specific

Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder worldwide after Alzheimer's disease for which available drugs only deliver temporary symptomatic relief. Loss of dopaminergic neurons (DaNs) in the substantia nigra and intracellular alpha-synuclein inclusions are the main hallmarks of the disease but the events that cause this degeneration remain uncertain. Despite cell types other than DaNs such as astrocytes, microglia and oligodendrocytes have been recently associated with the pathogenesis of PD, we still lack an in-depth characterisation of PD-affected brain regions at cell-type resolution that could help our understanding of the disease mechanisms. Nevertheless, publicly available large-scale brain-specific genomic, transcriptomic and epigenomic datasets can be further exploited to extract different layers of cell type-specific biological information for the reconstruction of cell type-specific transcriptional regulatory networks. By intersecting disease risk variants within the networks, it may be possible to study the functional role of these risk variants and their combined effects at cell type- and pathway levels, that, in turn, can facilitate the identification of key regulators involved in disease progression, which are often potential therapeutic targets.

scholarly journals Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

2019 ◽  
Author(s):  
Alexi Nott ◽  
Inge R. Holtman ◽  
Nicole G. Coufal ◽  
Johannes C.M. Schlachetzki ◽  
Miao Yu ◽  
...  
Keyword(s):  
Human Brain ◽  
Psychiatric Disorders ◽  
Complex Traits ◽  
Disease Risk ◽  
Cell Types ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Cell Type ◽  
Risk Variants ◽  
Cell Type Specific

AbstractUnique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological and psychiatric disorders. Here, we have defined active promoters and enhancers for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with regulatory regions in neurons, idiopathic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting GWAS variants in cell type-specific enhancers to gene promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable brain cell types in which they function.One Sentence SummaryIdentification of cell type-specific regulatory elements in the human brain enables interpretation of non-coding GWAS risk variants.

scholarly journals Brain cell type–specific enhancer–promoter interactome maps and disease-risk association

Science ◽  
2019 ◽  
Vol 366 (6469) ◽  
pp. 1134-1139 ◽  
Author(s):  
Alexi Nott ◽  
Inge R. Holtman ◽  
Nicole G. Coufal ◽  
Johannes C. M. Schlachetzki ◽  
Miao Yu ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Disease Risk ◽  
Phenotypic Diversity ◽  
Cell Types ◽  
Brain Cell ◽  
Brain Diseases ◽  
Cell Type ◽  
Functional Interpretation ◽  
Risk Variants ◽  
Cell Type Specific

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type–specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

Expression of the Ly-6 family proteins Lynx1 and Ly6H in the rat brain is compartmentalized, cell-type specific, and developmentally regulated

2013 ◽  
Vol 219 (6) ◽  
pp. 1923-1934 ◽  
Author(s):  
Morten Skøtt Thomsen ◽  
Betül Cinar ◽  
Majbrit Myrup Jensen ◽  
Ekaterina N. Lyukmanova ◽  
Mikhail A. Shulepko ◽  
...  
Keyword(s):  
Rat Brain ◽  
Cell Type ◽  
Developmentally Regulated ◽  
Cell Type Specific

scholarly journals Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits

2020 ◽  
Author(s):  
Nil Aygün ◽  
Angela L. Elwell ◽  
Dan Liang ◽  
Michael J. Lafferty ◽  
Kerry E. Cheek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Regulatory Mechanisms ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Expression ◽  
Risk Variants ◽  
Allele Specific ◽  
Cell Type Specific ◽  
Regulatory Effects

SummaryInterpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing is mainly performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements of cells present during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs and allele specific expression in primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74). Using colocalization and TWAS, we uncover cell-type specific regulatory mechanisms underlying risk for these traits.

scholarly journals Transcribed enhancers in the human brain identify novel disease risk mechanisms

2021 ◽  
Author(s):  
Pengfei Dong ◽  
Gabriel E. Hoffman ◽  
Pasha Apontes ◽  
Jaroslav Bendl ◽  
Samir Rahman ◽  
...  
Keyword(s):  
Human Brain ◽  
Disease Risk ◽  
Association Studies ◽  
Population Level ◽  
Cell Type ◽  
Level Variation ◽  
Functional Interpretation ◽  
Neuropsychiatric Diseases ◽  
Order Of Magnitude ◽  
Cell Type Specific

Enhancer RNAs (eRNAs) constitute an important tissue- and cell-type-specific layer of the regulome. Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding the population-level variation of eRNAs in the human brain. We jointly analyzed cell type-specific transcriptome and regulome data to identify 30,795 neuronal and 23,265 non-neuronal eRNAs, expanding the catalog of known human brain eRNAs by an order of magnitude. Examination of the population-level variation of the transcriptome and regulome in 1,382 brain samples identified reproducible changes affecting cis- and trans-co-regulation of eRNA-gene modules in schizophrenia. We show that 13% of schizophrenia heritability is jointly mediated in cis by brain gene and eRNA expression. Inclusion of eRNAs in transcriptome-wide association studies facilitated fine-mapping and functional interpretation of disease loci. Overall, our study characterizes the eRNA-gene regulome and genetic mechanisms in the human cortex in both healthy and disease states.

scholarly journals Semi-automated three-dimensional reconstructions of individual neurons reveal cell type-specific circuits in cortex

2011 ◽  
Vol 4 (4) ◽  
pp. 486-488 ◽  
Author(s):  
Zimbo S.R.M. Boudewijns ◽  
Tatjana Kleele ◽  
Huibert D. Mansvelder ◽  
Bert Sakmann ◽  
Christiaan P.J. de Kock ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Cell Type ◽  
Cell Type Specific

scholarly journals MSTD: an efficient method for detecting multi-scale topological domains from symmetric and asymmetric 3D genomic maps

2018 ◽  
Author(s):  
Yusen Ye ◽  
Lin Gao ◽  
Shihua Zhang
Keyword(s):  
Efficient Method ◽  
Three Dimensional ◽  
Cell Types ◽  
Cell Type ◽  
Range Interaction ◽  
Distinct Cell Type ◽  
Chromosome Conformation ◽  
Topological Domains ◽  
Multi Scale ◽  
Cell Type Specific

AbstractThe chromosome conformation capture (3C) technique and its variants have been employed to reveal the existence of a hierarchy of structures in three-dimensional (3D) chromosomal architecture, including compartments, topologically associating domains (TADs), sub-TADs and chromatin loops. However, existing methods for domain detection were only designed based on symmetric Hi-C maps, ignoring long-range interaction structures between domains. To this end, we proposed a generic and efficient method to identify multi-scale topological domains (MSTD), including cis- and trans-interacting regions, from a variety of 3D genomic datasets. We first applied MSTD to detect promoter-anchored interaction domains (PADs) from promoter capture Hi-C datasets across 17 primary blood cell types. The boundaries of PADs are significantly enriched with one or the combination of multiple epigenetic factors. Moreover, PADs between functionally similar cell types are significantly conserved in terms of domain regions and expression states. Cell type-specific PADs involve in distinct cell type-specific activities and regulatory events by dynamic interactions within them. We also employed MSTD to define multi-scale domains from typical symmetric Hi-C datasets and illustrated its distinct superiority to the-state-of-art methods in terms of accuracy, flexibility and efficiency.

scholarly journals Cell-type specific cis-eQTLs in eight brain cell-types identifies novel risk genes for human brain disorders

2021 ◽  
Author(s):  
Julien Bryois ◽  
Daniela Calini ◽  
Will Macnair ◽  
Lynette Foo ◽  
Eduard Urich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Risk ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Specific Cell ◽  
Eqtl Analysis ◽  
Cell Type ◽  
Disease Etiology ◽  
Risk Genes ◽  
Cell Type Specific

Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous brain tissues as opposed to specific cell types. To investigate the genetics of gene expression in adult human cell types from the central nervous system (CNS), we performed an eQTL analysis using single nuclei RNA-seq from 196 individuals in eight CNS cell types. We identified 6108 eGenes, a substantial fraction (43%, 2620 out of 6108) of which show cell-type specific effects, with strongest effects in microglia. Integration of CNS cell-type eQTLs with GWAS revealed novel relationships between expression and disease risk for neuropsychiatric and neurodegenerative diseases. For most GWAS loci, a single gene colocalized in a single cell type providing new clues into disease etiology. Our findings demonstrate substantial contrast in genetic regulation of gene expression among CNS cell types and reveal genetic mechanisms by which disease risk genes influence neurological disorders.

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