scholarly journals Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Science ◽  
2018 ◽  
Vol 362 (6420) ◽  
pp. eaat7615 ◽  
Author(s):  
Mingfeng Li ◽  
Gabriel Santpere ◽  
Yuka Imamura Kawasawa ◽  
Oleg V. Evgrafov ◽  
Forrest O. Gulden ◽  
...  
Keyword(s):  
Genomic Analysis ◽  
Cell Types ◽  
Brain Regions ◽  
Genetic Associations ◽  
Functional Genomic Analysis ◽  
Distinct Cell ◽  
Cell Type Specific ◽  
Epigenomic Regulation ◽  
Genomic Basis ◽  
Shaped Pattern

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type–specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

scholarly journals Simultaneous profiling of multiple chromatin proteins in the same cells

2021 ◽  
Author(s):  
Sneha Gopalan ◽  
Yuqing Wang ◽  
Nicholas W. Harper ◽  
Manuel Garber ◽  
Thomas G Fazzio
Keyword(s):  
Rna Polymerase Ii ◽  
Direct Analysis ◽  
Cell Types ◽  
Regulatory Elements ◽  
Genome Wide ◽  
Distinct Cell ◽  
Direct Measurements ◽  
Cell Type Specific ◽  
Chromatin Proteins

Methods derived from CUT&RUN and CUT&Tag enable genome-wide mapping of the localization of proteins on chromatin from as few as one cell. These and other mapping approaches focus on one protein at a time, preventing direct measurements of co-localization of different chromatin proteins in the same cells and requiring prioritization of targets where samples are limiting. Here we describe multi-CUT&Tag, an adaptation of CUT&Tag that overcomes these hurdles by using antibody-specific barcodes to simultaneously map multiple proteins in the same cells. Highly specific multi-CUT&Tag maps of histone marks and RNA Polymerase II uncovered sites of co-localization in the same cells, active and repressed genes, and candidate cis-regulatory elements. Single-cell multi-CUT&Tag profiling facilitated identification of distinct cell types from a mixed population and characterization of cell type-specific chromatin architecture. In sum, multi-CUT&Tag increases the information content per cell of epigenomic maps, facilitating direct analysis of the interplay of different proteins on chromatin.

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.

scholarly journals A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

2021 ◽  
Author(s):  
Shweta Ramdas ◽  
Jonathan Judd ◽  
Sarah E Graham ◽  
Stavroula Kanoni ◽  
Yuxuan Wang ◽  
...  
Keyword(s):  
Association Studies ◽  
Density Lipoprotein ◽  
Genomic Analysis ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Functional Genomic ◽  
Selective Enrichment ◽  
Functional Genomic Analysis

AbstractA major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.

scholarly journals Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Kapil Gupta ◽  
Christine Toelzer ◽  
Maia Kavanagh Williamson ◽  
Deborah K. Shoemark ◽  
A. Sofia F. Oliveira ◽  
...  
Keyword(s):  
Cell Types ◽  
Cell Tropism ◽  
Recognition Motif ◽  
Allosteric Communication ◽  
Distinct Cell ◽  
In The Wild ◽  
Evolutionary Trajectories ◽  
Cell Type Specific ◽  
Structural Insights ◽  
Insight Into

AbstractAs the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants with increased transmissibility and pathology. In addition to this entrenched diversity, RNA viruses can also display genetic diversity within single infected hosts with co-existing viral variants evolving differently in distinct cell types. The BriSΔ variant, originally identified as a viral subpopulation from SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike an eight amino-acid deletion encompassing a furin recognition motif and S1/S2 cleavage site. We elucidate the structure, function and molecular dynamics of this spike providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 receptor binding and infectivity of this SARS-CoV-2 variant. Our results reveal long-range allosteric communication between functional domains that differ in the wild-type and the deletion variant and support a view of SARS-CoV-2 probing multiple evolutionary trajectories in distinct cell types within the same infected host.

scholarly journals Structure and mechanism of SARS-CoV-2 Spike N679-V687 deletion variant elucidate cell-type specific evolution of viral fitness

2021 ◽  
Author(s):  
Kapil Gupta ◽  
Christine Toelzer ◽  
Maia Kavanagh Williamson ◽  
Deborah Shoemark ◽  
A. Sofia F. Oliveira ◽  
...  
Keyword(s):  
Cell Types ◽  
Viral Fitness ◽  
Cell Tropism ◽  
Cell Type ◽  
Amino Acid Deletion ◽  
Recognition Motif ◽  
Mechanistic Insight ◽  
Distinct Cell ◽  
Cell Type Specific ◽  
Insight Into

As the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants which is of particular concern due to their potential for increased transmissibility and pathology. In addition to this entrenched variant diversity in circulation, RNA viruses can also display genetic diversity within single infected hosts with co-existing viral variants evolving differently in distinct cell types. The BriSΔ variant, originally identified as a viral subpopulation by passaging SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike glycoprotein an eight amino-acid deletion encompassing the furin recognition motif and S1/S2 cleavage site. Here, we analyzed the structure, function and molecular dynamics of this variant spike, providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 receptor binding and infectivity, allowing the virus to probe diverse trajectories in distinct cell types to evolve viral fitness.

scholarly journals Addiction-associated genetic variants implicate brain cell type- and region-specific cis-regulatory elements in addiction neurobiology

2020 ◽  
Author(s):  
Chaitanya Srinivasan ◽  
BaDoi N. Phan ◽  
Alyssa J. Lawler ◽  
Easwaran Ramamurthy ◽  
Michael Kleyman ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Cell Types ◽  
Regulatory Elements ◽  
Brain Regions ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Coding Regions ◽  
Cell Type Specific ◽  
The Impact

ABSTRACTRecent large genome-wide association studies (GWAS) have identified multiple confident risk loci linked to addiction-associated behavioral traits. Genetic variants linked to addiction-associated traits lie largely in non-coding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied LD score regression to compare GWAS to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative regulatory elements marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known to play major roles in reward and addiction. To further dissect the cell type-specific basis of addiction-associated traits, we also identified enrichments in human orthologs of open chromatin regions of mouse neuron subtypes: cortical excitatory, PV, D1, and D2. Lastly, we developed machine learning models from mouse cell type-specific regions of open chromatin to further dissect human NeuN+ open chromatin regions into cortical excitatory or striatal D1 and D2 neurons and predict the functional impact of addiction-associated genetic variants. Our results suggest that different neuron subtypes within the reward system play distinct roles in the variety of traits that contribute to addiction.Significance StatementOur study on cell types and brain regions contributing to heritability of addiction-associated traits suggests that the conserved non-coding regions within cortical excitatory and striatal medium spiny neurons contribute to genetic predisposition for nicotine, alcohol, and cannabis use behaviors. This computational framework can flexibly integrate epigenomic data across species to screen for putative causal variants in a cell type- and tissue-specific manner across numerous complex traits.

scholarly journals Single-cell deconvolution of 3,000 post-mortem brain samples for eQTL and GWAS dissection in mental disorders

2021 ◽  
Author(s):  
Yongjin Park ◽  
Liang He ◽  
Jose Davila-Velderrain ◽  
Lei Hou ◽  
Shahin Mohammadi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Genetic Variants ◽  
Cell Types ◽  
Brain Regions ◽  
Post Mortem ◽  
Rna Seq ◽  
Cell Type ◽  
Post Mortem Brain ◽  
Cell Type Specific

AbstractThousands of genetic variants acting in multiple cell types underlie complex disorders, yet most gene expression studies profile only bulk tissues, making it hard to resolve where genetic and non-genetic contributors act. This is particularly important for psychiatric and neurodegenerative disorders that impact multiple brain cell types with highly-distinct gene expression patterns and proportions. To address this challenge, we develop a new framework, SPLITR, that integrates single-nucleus and bulk RNA-seq data, enabling phenotype-aware deconvolution and correcting for systematic discrepancies between bulk and single-cell data. We deconvolved 3,387 post-mortem brain samples across 1,127 individuals and in multiple brain regions. We find that cell proportion varies across brain regions, individuals, disease status, and genotype, including genetic variants in TMEM106B that impact inhibitory neuron fraction and 4,757 cell-type-specific eQTLs. Our results demonstrate the power of jointly analyzing bulk and single-cell RNA-seq to provide insights into cell-type-specific mechanisms for complex brain disorders.

Characterization and subcellular localization of a bacterial flotillin homologue

Microbiology ◽  
2009 ◽  
Vol 155 (6) ◽  
pp. 1786-1799 ◽  
Author(s):  
Catriona Donovan ◽  
Marc Bramkamp
Keyword(s):  
Early Stage ◽  
Model Organism ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Type ◽  
Distinct Cell ◽  
Sporulation Efficiency ◽  
Cell Type Specific ◽  
Detergent Resistant Membranes

The process of endospore formation in Bacillus subtilis is complex, requiring the generation of two distinct cell types, a forespore and larger mother cell. The development of these cell types is controlled and regulated by cell type-specific gene expression, activated by a σ-factor cascade. Activation of these cell type-specific sigma factors is coupled with the completion of polar septation. Here, we describe a novel protein, YuaG, a eukaryotic reggie/flotillin homologue that is involved in the early stages of sporulation of the Gram-positive model organism B. subtilis. YuaG localizes in discrete foci in the membrane and is highly dynamic. Purification of detergent-resistant membranes revealed that YuaG is associated with negatively charged phospholipids, e.g. phosphatidylglycerol (PG) or cardiolipin (CL). However, localization of YuaG is not always dependent on PG/CL in vivo. A yuaG disruption strain shows a delay in the onset of sporulation along with reduced sporulation efficiency, where the spores develop to a certain stage and then appear to be trapped at this stage. Our results indicate that YuaG is involved in the early stage of spore development, probably playing a role in the signalling cascade at the onset of sporulation.

scholarly journals Cell-Type-Specific Proteomics: A Neuroscience Perspective

Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 51 ◽  
Author(s):  
Rashaun S. Wilson ◽  
Angus C. Nairn
Keyword(s):  
Protein Detection ◽  
Analytical Techniques ◽  
Cell Types ◽  
Brain Regions ◽  
Cell Populations ◽  
Specific Cell ◽  
Cell Type ◽  
Specific Analysis ◽  
Cell Type Specific ◽  
Proteomics Research

Cell-type-specific analysis has become a major focus for many investigators in the field of neuroscience, particularly because of the large number of different cell populations found in brain tissue that play roles in a variety of developmental and behavioral disorders. However, isolation of these specific cell types can be challenging due to their nonuniformity and complex projections to different brain regions. Moreover, many analytical techniques used for protein detection and quantitation remain insensitive to the low amounts of protein extracted from specific cell populations. Despite these challenges, methods to improve proteomic yield and increase resolution continue to develop at a rapid rate. In this review, we highlight the importance of cell-type-specific proteomics in neuroscience and the technical difficulties associated. Furthermore, current progress and technological advancements in cell-type-specific proteomics research are discussed with an emphasis in neuroscience.

scholarly journals Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system

2021 ◽  
Vol 118 (8) ◽  
pp. e2011491118 ◽  
Author(s):  
Ekin Bolukbasi ◽  
Nathaniel S. Woodling ◽  
Dobril K. Ivanov ◽  
Jennifer Adcott ◽  
Andrea Foley ◽  
...  
Keyword(s):  
Nervous System ◽  
Transcription Factors ◽  
Cell Types ◽  
Growth Factor Signaling ◽  
Cell Type ◽  
Model Of Alzheimer’S Disease ◽  
Distinct Cell ◽  
Evolutionarily Conserved ◽  
Cell Type Specific ◽  
Specific Mapping

Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Drosophila. Starting from published single-cell transcriptomic data, we report that forkhead (FKH) is endogenously expressed in neurons, whereas forkhead-box-O (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer’s disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify Atg17, a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.

Sign in / Sign up

Export Citation Format

Share Document