scholarly journals The architecture of brain co-expression reveals the brain-wide basis of disease susceptibility

2020 ◽  
Author(s):  
CL Hartl ◽  
G Ramaswami ◽  
WG Pembroke ◽  
S Muller ◽  
G Pintacuda ◽  
...  
Keyword(s):  
Gene Networks ◽  
Regulatory Networks ◽  
Disease Risk ◽  
Cell Types ◽  
Brain Regions ◽  
Specific Cell ◽  
Risk Variants ◽  
Normal Individuals ◽  
Broad Array ◽  
The Brain

AbstractGene networks have proven their utility for elucidating transcriptome structure in the brain, yielding numerous biological insights. Most analyses have focused on expression relationships within a circumspect number of regions – how these relationships vary across a broad array of brain regions is largely unknown. By leveraging RNA-sequencing in 864 samples representing 12 brain regions in a cohort of 131 phenotypically normal individuals, we identify 12 brain-wide, 114 region-specific, and 50 cross-regional co-expression modules. We replicate the majority (81%) of modules in regional microarray datasets. Nearly 40% of expressed genes fall into brain-wide modules corresponding to major cell classes and conserved biological processes. Region-specific modules comprise 25% of expressed genes and correspond to region-specific cell types and processes, such as oxytocin signaling in the hypothalamus, or addiction pathways in the nucleus accumbens. We further leverage these modules to capture cell-type-specific lncRNA and gene isoforms, both of which contribute substantially to regional synaptic diversity. We identify enrichment of neuropsychiatric disease risk variants in brain wide and multi-regional modules, consistent with their broad impact on cell classes, and highlight specific roles in neuronal proliferation and activity-dependent processes. Finally, we examine the manner in which gene co-expression and gene regulatory networks reflect genetic risk, including the recently framed omnigenic model of disease architecture.

scholarly journals MRI of Capn15 knockout mice and analysis of Capn15 distribution reveal possible roles in brain development and plasticity

2019 ◽  
Author(s):  
Congyao Zha ◽  
Carole A Farah ◽  
Vladimir Fonov ◽  
David A. Rudko ◽  
Wayne S Sossin
Keyword(s):  
Brain Development ◽  
Knockout Mice ◽  
Brain Plasticity ◽  
Small Animal ◽  
Cell Types ◽  
Cysteine Proteases ◽  
Brain Regions ◽  
Conditional Knockout ◽  
Specific Cell ◽  
The Brain

AbstractPurposeThe non-classical Small Optic Lobe (SOL) family of calpains are intracellular cysteine proteases that are expressed in the nervous system and appear to play an important role in neuronal development in both Drosophila, where loss of this calpain leads to the eponymous small optic lobes, and in mouse and human, where loss of this calpain (Capn15) leads to eye anomalies. However, the brain regions where this calpain is expressed and the areas most affected by the loss of this calpain have not been carefully examined.ProceduresWe utilize an insert strain where lacZ is expressed under the control of the Capn15 promoter, together with immunocytochemistry with markers of specific cell types to address where Capn 15 is expressed in the brain. We use small animal MRI comparing WT, Capn15 knockout and Capn15 conditional knockout mice to address the brain regions that are affected when Capn 15 is not present, either in early development of the adult.ResultsCapn15 is expressed in diverse brain regions, many of them involved in plasticity such as the hippocampus, lateral amygdala and Purkinje neurons. Capn15 knockout mice have smaller brains, and present specific deficits in the thalamus and hippocampal regions. There are no deficits revealed by MRI in brain regions when Capn15 is knocked out after development.ConclusionsAreas where Capn15 is expressed in the adult are not good markers for the specific regions where the loss of Capn15 specifically affects brain development. Thus, it is likely that this calpain plays distinct roles in brain development and brain plasticity.

scholarly journals Integrative analysis of multi-omics reveals gene regulatory networks across brain regions from risk variants to phenotypes of Alzheimer’s disease and Covid-19

2021 ◽  
Author(s):  
Saniya Khullar ◽  
Daifeng Wang
Keyword(s):  
Disease Progression ◽  
Temporal Lobe ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Disease Risk ◽  
Regulatory Elements ◽  
Brain Regions ◽  
Risk Variants ◽  
Gene Regulatory

AbstractBackgroundGenome-wide association studies have found many genetic risk variants associated with Alzheimer’s disease (AD). However, how these risk variants affect deeper phenotypes such as disease progression and immune response remains elusive. Also, our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. To address these problems, we performed integrative multi-omics analysis from genotype, transcriptomics, and epigenomics for revealing gene regulatory mechanisms from disease variants to AD phenotypes.MethodFirst, we cluster gene co-expression networks and identify gene modules for various AD phenotypes given population gene expression data. Next, we predict the transcription factors (TFs) that significantly regulate the genes in each module and the AD risk variants (e.g., SNPs) interrupting the TF binding sites on the regulatory elements. Finally, we construct a full gene regulatory network linking SNPs, interrupted TFs, and regulatory elements to target genes for each phenotype. This network thus provides mechanistic insights of gene regulation from disease risk variants to AD phenotypes.ResultsWe applied our analysis to predict the gene regulatory networks in three major AD-relevant regions: hippocampus, dorsolateral prefrontal cortex (DLPFC), and lateral temporal lobe (LTL). These region networks provide a comprehensive functional genomic map linking AD SNPs to TFs and regulatory elements to target genes for various AD phenotypes. Comparative analyses further revealed cross-region-conserved and region-specific regulatory networks. For instance, AD SNPs rs13404184 and rs61068452 disrupt the bindings of TF SPI1 that regulates AD gene INPP5D in the hippocampus and lateral temporal lobe. However, SNP rs117863556 interrupts the bindings of TF REST to regulate GAB2 in the DLPFC only. Furthermore, driven by recent discoveries between AD and Covid-19, we found that many genes from our networks regulating Covid-19 pathways are also significantly differentially expressed in severe Covid patients (ICU), suggesting potential regulatory connections between AD and Covid. Thus, we used the machine learning models to predict severe Covid and prioritized highly predictive genes as AD-Covid genes. We also used Decision Curve Analysis to show that our AD-Covid genes outperform known Covid-19 genes for predicting Covid severity and deciding to send patients to ICU or not. In short, our results provide a deeper understanding of the interplay among multi-omics, brain regions, and AD phenotypes, including disease progression and Covid response. Our analysis is open-source available at https://github.com/daifengwanglab/ADSNPheno.

scholarly journals Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution

2020 ◽  
Author(s):  
M. J. Higgs ◽  
M. J. Hill ◽  
R. M. John ◽  
A. R. Isles
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Gene Networks ◽  
Cell Types ◽  
Brain Regions ◽  
Systematic Investigation ◽  
Adult Brain ◽  
Imprinted Genes ◽  
Imprinted Gene ◽  
The Brain

AbstractAlthough a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using fifteen single-cell RNA sequencing datasets we take a systematic approach to investigate imprinted gene over-representation at the organ, brain region, and cell-specific levels. We establish that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types. We then examine brain-wide datasets to examine enrichment within distinct regions of the brain and demonstrate over-representation of imprinted genes in the hypothalamus, ventral midbrain, pons and medulla. Finally, using datasets focusing on these regions of enrichment, we were able to identify hypothalamic neuroendocrine populations and the monoaminergic hindbrain neurons as specific hotspots of imprinted gene expression. These analyses provide the first robust assessment of the neural systems on which imprinted genes converge. Moreover, the unbiased approach, with each analysis informed by the findings of the previous level, permits highly informed inferences about the functions on which imprinted genes converge. Our findings indicate the neuronal regulation of motivated behaviours such as feeding, parental behaviour and sleep as functional hotspots for imprinting, thus adding statistically rigour to prior assumptions and providing testable predictions for novel neural and behavioural phenotypes associated with specific genes and imprinted gene networks. In turn, this work sheds further light on the potential evolutionary drivers of genomic imprinting in the brain.

scholarly journals From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130542 ◽  
Author(s):  
David-Emlyn Parfitt ◽  
Michael M. Shen
Keyword(s):  
Stem Cells ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Network Models ◽  
Cell Types ◽  
Mammalian Development ◽  
A Genome

To date, many regulatory genes and signalling events coordinating mammalian development from blastocyst to gastrulation stages have been identified by mutational analyses and reverse-genetic approaches, typically on a gene-by-gene basis. More recent studies have applied bioinformatic approaches to generate regulatory network models of gene interactions on a genome-wide scale. Such models have provided insights into the gene networks regulating pluripotency in embryonic and epiblast stem cells, as well as cell-lineage determination in vivo . Here, we review how regulatory networks constructed for different stem cell types relate to corresponding networks in vivo and provide insights into understanding the molecular regulation of the blastocyst–gastrula transition.

scholarly journals Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

2019 ◽  
Author(s):  
Jennifer K. Forsyth ◽  
Daniel Nachun ◽  
Michael J. Gandal ◽  
Daniel H. Geschwind ◽  
Ariana E. Anderson ◽  
...  
Keyword(s):  
Gene Networks ◽  
Disease Risk ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Protein Interaction Data ◽  
Regulatory Pathways ◽  
Polygenic Risk ◽  
Risk Variants ◽  
Gene Regulatory

AbstractBackground22q11.2 copy number variants (CNVs) are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear.MethodsUsing a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and pathophysiological signatures of SCZ and ASD to: 1) organize genes into the developmental cellular and molecular systems within which they operate; 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum; and 3) elucidate pathways and individual genes through which 22q11.2 CNVs may confer risk for each disorder.ResultsPolygenic risk for SCZ and ASD converged on partially overlapping gene networks involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for networks involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network that disproportionately affected SCZ- and ASD-associated neurodevelopmental networks, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation.ConclusionsThe current approach provides a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD, and elucidate the mechanisms through which highly penetrant multi-gene CNVs contribute to disease risk.

scholarly journals Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

2021 ◽  
Vol 15 ◽  
Author(s):  
Louis-Philippe Bernier ◽  
Clément Brunner ◽  
Azzurra Cottarelli ◽  
Matilde Balbi
Keyword(s):  
Brain Function ◽  
Energy Demand ◽  
Neurovascular Unit ◽  
Cell Types ◽  
Brain Regions ◽  
Regional Heterogeneity ◽  
Regional Specialization ◽  
Multiple Cell ◽  
Cellular Components ◽  
The Brain

The neurovascular unit (NVU) of the brain is composed of multiple cell types that act synergistically to modify blood flow to locally match the energy demand of neural activity, as well as to maintain the integrity of the blood-brain barrier (BBB). It is becoming increasingly recognized that the functional specialization, as well as the cellular composition of the NVU varies spatially. This heterogeneity is encountered as variations in vascular and perivascular cells along the arteriole-capillary-venule axis, as well as through differences in NVU composition throughout anatomical regions of the brain. Given the wide variations in metabolic demands between brain regions, especially those of gray vs. white matter, the spatial heterogeneity of the NVU is critical to brain function. Here we review recent evidence demonstrating regional specialization of the NVU between brain regions, by focusing on the heterogeneity of its individual cellular components and briefly discussing novel approaches to investigate NVU diversity.

scholarly journals Cardiac Cell Type-Specific Gene Regulatory Programs and Disease Risk Association

2020 ◽  
Author(s):  
James D. Hocker ◽  
Olivier B. Poirion ◽  
Fugui Zhu ◽  
Justin Buchanan ◽  
Kai Zhang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Cell Types ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Dependent Manner ◽  
Cardiac Cell ◽  
Risk Variants ◽  
Gene Regulatory

ABSTRACTBackgroundCis-regulatory elements such as enhancers and promoters are crucial for directing gene expression in the human heart. Dysregulation of these elements can result in many cardiovascular diseases that are major leading causes of morbidity and mortality worldwide. In addition, genetic variants associated with cardiovascular disease risk are enriched within cis-regulatory elements. However, the location and activity of these cis-regulatory elements in individual cardiac cell types remains to be fully defined.MethodsWe performed single nucleus ATAC-seq and single nucleus RNA-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) and gene expression patterns for the distinct cell types comprising each chamber of four non-failing human hearts. We used this catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants.ResultsWe defined >287,000 candidate cis-regulatory elements (cCREs) in human hearts at single-cell resolution, which notably revealed gene regulatory programs controlling specific cell types in a cardiac region/structure-dependent manner and during heart failure. We further report enrichment of cardiovascular disease risk variants in cCREs of distinct cardiac cell types, including a strong enrichment of atrial fibrillation variants in cardiomyocyte cCREs, and reveal 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele. Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner.ConclusionsThis comprehensive atlas of human cardiac cCREs provides the foundation for not only illuminating cell type-specific gene regulatory programs controlling human hearts during health and disease, but also interpreting genetic risk loci for a wide spectrum of cardiovascular diseases.

scholarly journals STAB: a spatio-temporal cell atlas of the human brain

2020 ◽  
Vol 49 (D1) ◽  
pp. D1029-D1037
Author(s):  
Liting Song ◽  
Shaojun Pan ◽  
Zichao Zhang ◽  
Longhao Jia ◽  
Wei-Hua Chen ◽  
...  
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Temporal Dynamics ◽  
Cell Types ◽  
Brain Regions ◽  
Molecular Characteristics ◽  
Great Effort ◽  
Brain Functions ◽  
Spatio Temporal ◽  
The Brain

Abstract The human brain is the most complex organ consisting of billions of neuronal and non-neuronal cells that are organized into distinct anatomical and functional regions. Elucidating the cellular and transcriptome architecture underlying the brain is crucial for understanding brain functions and brain disorders. Thanks to the single-cell RNA sequencing technologies, it is becoming possible to dissect the cellular compositions of the brain. Although great effort has been made to explore the transcriptome architecture of the human brain, a comprehensive database with dynamic cellular compositions and molecular characteristics of the human brain during the lifespan is still not available. Here, we present STAB (a Spatio-Temporal cell Atlas of the human Brain), a database consists of single-cell transcriptomes across multiple brain regions and developmental periods. Right now, STAB contains single-cell gene expression profiling of 42 cell subtypes across 20 brain regions and 11 developmental periods. With STAB, the landscape of cell types and their regional heterogeneity and temporal dynamics across the human brain can be clearly seen, which can help to understand both the development of the normal human brain and the etiology of neuropsychiatric disorders. STAB is available at http://stab.comp-sysbio.org.

scholarly journals The HIV-1 Transgenic Rat: Relevance for HIV Noninfectious Comorbidity Research

2020 ◽  
Vol 8 (11) ◽  
pp. 1643
Author(s):  
Frank Denaro ◽  
Francesca Benedetti ◽  
Myla D. Worthington ◽  
Giovanni Scapagnini ◽  
Christopher C. Krauss ◽  
...  
Keyword(s):  
Neuronal Degeneration ◽  
Cell Types ◽  
Transgenic Rat ◽  
Specific Cell ◽  
Rat Tissues ◽  
Local Production ◽  
Specific Tissue ◽  
Effective Models ◽  
The Brain ◽  
Hiv 1

HIV noninfectious comorbidities (NICMs) are a current healthcare challenge. The situation is further complicated as there are very few effective models that can be used for NICM research. Previous research has supported the use of the HIV-1 transgenic rat (HIV-1TGR) as a model for the study of HIV/AIDS. However, additional studies are needed to confirm whether this model has features that would support NICM research. A demonstration of the utility of the HIV-1TGR model would be to show that the HIV-1TGR has cellular receptors able to bind HIV proteins, as this would be relevant for the study of cell-specific tissue pathology. In fact, an increased frequency of HIV receptors on a specific cell type may increase tissue vulnerability since binding to HIV proteins would eventually result in cell dysfunction and death. Evidence suggests that observations of selective cellular vulnerability in this model are consistent with some specific tissue vulnerabilities seen in NICMs. We identified CXCR4-expressing cells in the brain, while specific markers for neuronal degeneration demonstrated that the same neural types were dying. We also confirm the presence of gp120 and Tat by immunocytochemistry in the spleen, as previously reported. However, we observed very rare positive cells in the brain. This underscores the point that gp120, which has been reported as detected in the sera and CSF, is a likely source to which these CXCR4-positive cells are exposed. This alternative appears more probable than the local production of gp120. Further studies may indicate some level of local production, but that will not eliminate the role of receptor-mediated pathology. The binding of gp120 to the CXCR4 receptor on neurons and other neural cell types in the HIV-1TGR can thus explain the phenomena of selective cell death. Selective cellular vulnerability may be a contributing factor to the development of NICMs. Our data indicate that the HIV-1TGR can be an effective model for the studies of HIV NICMs because of the difference in the regional expression of CXCR4 in rat tissues, thus leading to specific organ pathology. This also suggests that the model can be used in the development of therapeutic options.

Three-Dimensional Time-Lapse Digital Movie Analysis of the Developing Fruit Fly Eye in Organ Culture

1997 ◽  
Vol 3 (S2) ◽  
pp. 1129-1130
Author(s):  
John Archie Pollock ◽  
Bejon T. Maneckshana ◽  
Teresa E. Leonardo
Keyword(s):  
Organ Culture ◽  
Compound Eye ◽  
Eye Development ◽  
Larval Instar ◽  
Three Dimensional ◽  
Fruit Fly ◽  
Time Lapse ◽  
Cell Types ◽  
Specific Cell ◽  
The Brain

The compound eye of the fruit fly, Drosophila melanogaster, is composed of a highly ordered array of facets (FIG. 1), each containing a precise set of neurons and supporting cells. The eye arises during the third larval instar from an undifferentiated epithelium, the eye imaginai disc, which is connected to the brain via the optic stalk (FIG. 2). During eye development, movement of the morphogenetic furrow, progressive recruitment of specific cell types and the growth of photoreceptor axons into the brain are each dynamic processes that are routinely studied indirectly in fixed tissues. While stereotyped development and the ‘crystalline’ like structure of the eye facilitates this analysis, certain experiments are hindered by the inability to observe developmental processes as they occur. To overcome this limitation, we have combined organ culture with advanced microscopy tools to enable the observation of eye development in living tissue.

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