scholarly journals Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

2021 ◽  
Author(s):  
Dan Liang ◽  
Angela L. Elwell ◽  
Nil Aygün ◽  
Oleh Krupa ◽  
Justin M. Wolter ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Neuronal Differentiation ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Specific Effects ◽  
Cell Type Specific

scholarly journals Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

2020 ◽  
Author(s):  
Dan Liang ◽  
Angela L. Elwell ◽  
Nil Aygün ◽  
Michael J. Lafferty ◽  
Oleh Krupa ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Neural Progenitor Cells ◽  
Cortical Development ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Mechanisms ◽  
List Type ◽  
Cell Type ◽  
Specific Effects ◽  
Cell Type Specific

SummaryCommon genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, the mechanisms mediating the effects of genetic variants on gene regulation are poorly understood. To determine the functional impact of common genetic variation on the non-coding genome longitudinally during human cortical development, we performed a chromatin accessibility quantitative trait loci (caQTL) analysis in neural progenitor cells and their differentiated neuronal progeny from 92 donors. We identified 8,111 caQTLs in progenitors and 3,676 caQTLs in neurons, with highly temporal, cell-type specific effects. A subset (∼20%) of caQTLs were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type specific caQTLs and brain-relevant genome-wide association data, we were able to fine-map loci and identify regulatory mechanisms underlying non-coding neuropsychiatric disorder risk variants.HighlightsGenetic variation alters chromatin architecture during human cortical developmentGenetic effects on chromatin accessibility are highly cell-type specificAlleles disrupting TF motifs generally decrease accessibility, except for repressorscaQTLs facilitate fine-mapping and inference of regulatory mechanisms of GWAS loci

scholarly journals Identification of genomic enhancers through spatial integration of single-cell transcriptomics and epigenomics

2019 ◽  
Author(s):  
Carmen Bravo González-Blas ◽  
Xiao-Jiang Quan ◽  
Ramon Duran-Romaña ◽  
Ibrahim Ihsan Taskiran ◽  
Duygu Koldere ◽  
...  
Keyword(s):  
Single Cell ◽  
Regulatory Networks ◽  
Chromatin Accessibility ◽  
Virtual Space ◽  
Spatial Integration ◽  
Cell Type ◽  
Enhancer Activity ◽  
Specific Effects ◽  
Bona Fide ◽  
Cell Type Specific

AbstractSingle-cell technologies allow measuring chromatin accessibility and gene expression in each cell, but jointly utilizing both layers to map bona fide gene regulatory networks and enhancers remains challenging. Here, we generate independent single-cell RNA-seq and single-cell ATAC-seq atlases of the Drosophila eye-antennal disc and spatially integrate the data using a virtual latent space that mimics the organization of the 2D tissue. To validate spatially predicted enhancers, we use a large collection of enhancer-reporter lines and identify ∼85% of enhancers in which chromatin accessibility and enhancer activity are coupled. Next, we infer enhancer-to-gene relationships in the virtual space, finding that genes are regulated by multiple redundant enhancers. Exploiting cell-type specific enhancers, we deconvolute cell-type specific effects of bulk-derived chromatin accessibility QTLs. Finally, we discover that Prospero drives neuronal differentiation through the binding of a GGG motif. In summary, we provide a comprehensive spatial characterization of gene regulation in a 2D tissue.

scholarly journals Low Replicative Stress Triggers Cell-Type Specific Inheritable Advanced Replication Timing

2021 ◽  
Vol 22 (9) ◽  
pp. 4959
Author(s):  
Lilas Courtot ◽  
Elodie Bournique ◽  
Chrystelle Maric ◽  
Laure Guitton-Sert ◽  
Miguel Madrid-Mencía ◽  
...  
Keyword(s):  
Replication Timing ◽  
Replication Stress ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Replicative Stress ◽  
Daughter Cells ◽  
Origin Activation ◽  
Cell Type Specific ◽  
Cellular Identity ◽  
Dna Replication Timing

DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin. We report that RT advances are cell-type-specific and involve large heterochromatin domains. Importantly, we found that some major late to early RT advances can be inherited by the unstressed next-cellular generation, which is a unique process that correlates with enhanced chromatin accessibility, as well as modified replication origin landscape and gene expression in daughter cells. Collectively, this work highlights how low replication stress may impact cellular identity by RT advances events at a subset of chromosomal domains.

scholarly journals Cell type-specific effects ofYersinia pseudotuberculosisvirulence effectors

2009 ◽  
Vol 11 (12) ◽  
pp. 1750-1767 ◽  
Author(s):  
Anna Fahlgren ◽  
Linda Westermark ◽  
Karen Akopyan ◽  
Maria Fällman
Keyword(s):  
Cell Type ◽  
Specific Effects ◽  
Cell Type Specific

scholarly journals Cell type-specific effects of isoflurane on two distinct afferent inputs to cortical layer 1

2020 ◽  
Author(s):  
Caitlin A. Murphy ◽  
Matthew I. Banks
Keyword(s):  
Ex Vivo ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Cellular Level ◽  
Cortical Layer ◽  
Cell Type ◽  
Specific Effects ◽  
Primary Mouse ◽  
Cell Type Specific ◽  
Synaptic Responses

ABSTRACTBackgroundWhile their behavioral effects are well-characterized, the mechanisms by which anaesthetics induce loss of consciousness are largely unknown. Anaesthetics may disrupt integration and propagation of information in corticothalamic networks. Recent studies have shown that isoflurane diminishes synaptic responses of thalamocortical (TC) and corticocortical (CC) afferents in a pathway-specific manner. However, whether the synaptic effects of isoflurane observed in extracellular recordings persist at the cellular level has yet to be explored.MethodsHere, we activate TC and CC layer 1 inputs in non-primary mouse neocortex in ex vivo brain slices and explore the degree to which isoflurane modulates synaptic responses in pyramidal cells and in two inhibitory cell populations, somatostatin-positive (SOM+) and parvalbumin-positive (PV+) interneurons.ResultsWe show that the effects of isoflurane on synaptic responses and intrinsic properties of these cells varies among cell type and by cortical layer. Layer 1 inputs to L4 pyramidal cells were suppressed by isoflurane at both TC and CC synapses, while those to L2/3 pyramidal cells and PV+ interneurons were not. TC inputs to SOM+ cells were rarely observed at all, while CC inputs to SOM+ interneurons were robustly suppressed by isoflurane.ConclusionsThese results suggest a mechanism by which isoflurane disrupts integration and propagation of thalamocortical and intracortical signals.

Cell type-specific effects of BDNF in modulating dendritic architecture of hippocampal neurons

2018 ◽  
Vol 223 (8) ◽  
pp. 3689-3709 ◽  
Author(s):  
Marta Zagrebelsky ◽  
N. Gödecke ◽  
A. Remus ◽  
Martin Korte
Keyword(s):  
Hippocampal Neurons ◽  
Cell Type ◽  
Specific Effects ◽  
Cell Type Specific

scholarly journals Cell type-specific effects of p27KIP1 loss on retinal development

2017 ◽  
Vol 12 (1) ◽  
Author(s):  
Mariko Ogawa ◽  
Fuminori Saitoh ◽  
Norihiro Sudou ◽  
Fumi Sato ◽  
Hiroki Fujieda
Keyword(s):  
Retinal Development ◽  
Cell Type ◽  
Specific Effects ◽  
Cell Type Specific

scholarly journals Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility

2018 ◽  
Vol 115 (5) ◽  
pp. 1111-1116 ◽  
Author(s):  
Mitra Heshmati ◽  
Hossein Aleyasin ◽  
Caroline Menard ◽  
Daniel J. Christoffel ◽  
Meghan E. Flanigan ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Cell Type ◽  
Dopamine D2 ◽  
Disease States ◽  
Specific Effects ◽  
Chronic Social Defeat Stress ◽  
Cell Type Specific ◽  
Stress Susceptibility ◽  
Cell Adhesion Proteins

Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.

scholarly journals Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Nathaniel S. Woodling ◽  
Arjunan Rajasingam ◽  
Lucy J. Minkley ◽  
Alberto Rizzo ◽  
Linda Partridge
Keyword(s):  
Glial Cell ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Developmental Timing ◽  
Cell Type ◽  
Specific Effects ◽  
Trade Offs ◽  
Distinct Cell ◽  
Pi3k Signalling ◽  
Cell Type Specific

Abstract Background The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases. The highly conserved diversity of neuronal and non-neuronal (glial) cell types in the Drosophila nervous system makes it an attractive system to address this possibility. We have thus investigated whether IIS in distinct glial cell populations differentially modulates development and lifespan in Drosophila. Results We report here that glia-specific IIS inhibition, using several genetic means, delays development while extending healthy lifespan. The effects on lifespan can be recapitulated by adult-onset IIS inhibition, whereas developmental IIS inhibition is dispensable for modulation of lifespan. Notably, the effects we observe on both lifespan and development act through the PI3K branch of the IIS pathway and are dependent on the transcription factor FOXO. Finally, IIS inhibition in several glial subtypes can delay development without extending lifespan, whereas the same manipulations in astrocyte-like glia alone are sufficient to extend lifespan without altering developmental timing. Conclusions These findings reveal a role for distinct glial subpopulations in the organism-wide modulation of development and lifespan, with IIS in astrocyte-like glia contributing to lifespan modulation but not to developmental timing. Our results enable a more complete picture of the cell-type-specific effects of the IIS network, a pathway whose evolutionary conservation in humans make it tractable for therapeutic interventions. Our findings therefore underscore the necessity for cell-type-specific strategies to optimise interventions for the diseases of ageing.

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