scholarly journals Pubertal sex hormones control transcriptional trajectories in the medial preoptic area

2021 ◽  
Author(s):  
Koichi Hashikawa ◽  
Yoshiko Hashikawa ◽  
Yuejia Liu ◽  
Mark Rossi ◽  
Marcus Basiri ◽  
...  
Keyword(s):  
Preoptic Area ◽  
Cell Types ◽  
Medial Preoptic Area ◽  
Sexually Dimorphic ◽  
Cell Type ◽  
Reproductive Behaviors ◽  
Transcriptional Dynamics ◽  
Cell Type Specific ◽  
Gene Regulatory ◽  
Adolescent Brain Development

Pubertal maturation aids development of emotion, cognition, and reproduction. We investigated transcriptional dynamics in the medial preoptic area (MPOA), a hypothalamic center for reproductive behaviors, in male and female mice at single-cell resolution (scRNAseq) during puberty. Defined subsets of neurons expressing Slc32a1 and Esr1 (Vgat+ Esr1+) were the most transcriptionally dynamic compared to other cell types throughout puberty. These cell type specific transcriptional progressions towards adulthood were bidirectionally controlled by the levels of circulating testosterone and estradiol. Selective deletion of Esr1 in Slc32a1-expressing cells in the MPOA prior to puberty arrested transcriptional progression and revealed a sexually dimorphic gene-regulatory network governed by Esr1. Deletion of Esr1 in Vgat+ cells prevented the development of mating behavior in both sexes. These analyses reveal both sexually common and dimorphic transcriptional progressions during puberty as well as their regulatory mechanisms, which have important implications towards understanding adaptative and maladaptive processes governing adolescent brain development.

scholarly journals Predicting gene regulatory networks from cell atlases

2020 ◽  
Author(s):  
Andreas Fønss Møller ◽  
Kedar Nath Natarajan
Keyword(s):  
Single Cell ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Types ◽  
Mouse Cell ◽  
Cell Type ◽  
Integrated Network ◽  
Mouse Tissues ◽  
Cell Type Specific ◽  
Gene Regulatory

AbstractRecent single-cell RNA-sequencing atlases have surveyed and identified major cell-types across different mouse tissues. Here, we computationally reconstruct gene regulatory networks from 3 major mouse cell atlases to capture functional regulators critical for cell identity, while accounting for a variety of technical differences including sampled tissues, sequencing depth and author assigned cell-type labels. Extracting the regulatory crosstalk from mouse atlases, we identify and distinguish global regulons active in multiple cell-types from specialised cell-type specific regulons. We demonstrate that regulon activities accurately distinguish individual cell types, despite differences between individual atlases. We generate an integrated network that further uncovers regulon modules with coordinated activities critical for cell-types, and validate modules using available experimental data. Inferring regulatory networks during myeloid differentiation from wildtype and Irf8 KO cells, we uncover functional contribution of Irf8 regulon activity and composition towards monocyte lineage. Our analysis provides an avenue to further extract and integrate the regulatory crosstalk from single-cell expression data.SummaryIntegrated single-cell gene regulatory network from three mouse cell atlases captures global and cell-type specific regulatory modules and crosstalk, important for cellular identity.

scholarly journals Complex transcriptional regulation and independent evolution of fungal-like traits in a relative of animals

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Alex de Mendoza ◽  
Hiroshi Suga ◽  
Jon Permanyer ◽  
Manuel Irimia ◽  
Iñaki Ruiz-Trillo
Keyword(s):  
Cell Types ◽  
Cell Type ◽  
Dynamic Regulation ◽  
Transcriptional Dynamics ◽  
Genome Regulation ◽  
A Cell ◽  
Cell Type Specific ◽  
Gene Modules ◽  
Multicellular Organisms ◽  
Different Cell Types

Cell-type specification through differential genome regulation is a hallmark of complex multicellularity. However, it remains unclear how this process evolved during the transition from unicellular to multicellular organisms. To address this question, we investigated transcriptional dynamics in the ichthyosporean Creolimax fragrantissima, a relative of animals that undergoes coenocytic development. We find that Creolimax utilizes dynamic regulation of alternative splicing, long inter-genic non-coding RNAs and co-regulated gene modules associated with animal multicellularity in a cell-type specific manner. Moreover, our study suggests that the different cell types of the three closest animal relatives (ichthyosporeans, filastereans and choanoflagellates) are the product of lineage-specific innovations. Additionally, a proteomic survey of the secretome reveals adaptations to a fungal-like lifestyle. In summary, the diversity of cell types among protistan relatives of animals and their complex genome regulation demonstrates that the last unicellular ancestor of animals was already capable of elaborate specification of cell types.

scholarly journals ANANSE: An enhancer network-based computational approach for predicting key transcription factors in cell fate determination

2020 ◽  
Author(s):  
Quan Xu ◽  
Georgios Georgiou ◽  
Gert Jan C. Veenstra ◽  
Huiqing Zhou ◽  
Simon J. van Heeringen
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Types ◽  
Cell Fate Determination ◽  
Cell Type ◽  
Fate Determination ◽  
Cell Type Specific ◽  
Gene Regulatory

AbstractProper cell fate determination is largely orchestrated by complex gene regulatory networks centered around transcription factors. However, experimental elucidation of key transcription factors that drive cellular identity is currently often intractable. Here, we present ANANSE (ANalysis Algorithm for Networks Specified by Enhancers), a network-based method that exploits enhancer-encoded regulatory information to identify the key transcription factors in cell fate determination. As cell type-specific transcription factors predominantly bind to enhancers, we use regulatory networks based on enhancer properties to prioritize transcription factors. First, we predict genome-wide binding profiles of transcription factors in various cell types using enhancer activity and transcription factor binding motifs. Subsequently, applying these inferred binding profiles, we construct cell type-specific gene regulatory networks, and then predict key transcription factors controlling cell fate conversions using differential gene networks between cell types. This method outperforms existing approaches in correctly predicting major transcription factors previously identified to be sufficient for trans-differentiation. Finally, we apply ANANSE to define an atlas of key transcription factors in 18 normal human tissues. In conclusion, we present a ready-to-implement computational tool for efficient prediction of transcription factors in cell fate determination and to study transcription factor-mediated regulatory mechanisms. ANANSE is freely available at https://github.com/vanheeringen-lab/ANANSE.

scholarly journals Single-cell network biology characterizes cell-type gene regulation for drug repurposing and phenotype prediction in Alzheimer's disease

2022 ◽  
Author(s):  
Chirag Gupta ◽  
Jielin Xu ◽  
Ting Jin ◽  
Saniya Khullar ◽  
Xiaoyu Liu ◽  
...  
Keyword(s):  
Single Cell ◽  
Regulatory Networks ◽  
Cell Types ◽  
Network Biology ◽  
Cell Type ◽  
Cell Network ◽  
Cell Type Specific ◽  
Gene Regulatory ◽  
Type Gene ◽  
And Control

Dysregulation of gene expression in Alzheimer's disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern target gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, it is still challenging to understand how cell type networks work abnormally under AD. To address this, we integrated single-cell multi-omics data and predicted the gene regulatory networks in AD and control for four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes. Importantly, we applied network biology approaches to analyze the changes of network characteristics across these cell types, and between AD and control. For instance, many hub TFs target different genes between AD and control (rewiring). Also, these networks show strong hierarchical structures in which top TFs (master regulators) are largely common across cell types, whereas different TFs operate at the middle levels in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed-forward loops) further uncover cell-type-specific TF-TF cooperativities in gene regulation. The cell type networks are highly modular. Several network modules with cell-type-specific expression changes in AD pathology are enriched with AD-risk genes and putative targets of approved and pending AD drugs, suggesting possible cell-type genomic medicine in AD. Finally, using the cell type gene regulatory networks, we developed machine learning models to classify and prioritize additional AD genes. We found that top prioritized genes predict clinical phenotypes (e.g., cognitive impairment). Overall, this single-cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals mechanisms on cell-type gene dyregulation in AD.

scholarly journals Epigenetic reprogramming of cell identity: lessons from development for regenerative medicine

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Amitava Basu ◽  
Vijay K. Tiwari
Keyword(s):  
Regenerative Medicine ◽  
Cell Types ◽  
Direct Conversion ◽  
Cellular Reprogramming ◽  
Specific Cell ◽  
Cell Type ◽  
Pathological Conditions ◽  
Gene Regulatory ◽  
Induced Pluripotent ◽  
And Function

AbstractEpigenetic mechanisms are known to define cell-type identity and function. Hence, reprogramming of one cell type into another essentially requires a rewiring of the underlying epigenome. Cellular reprogramming can convert somatic cells to induced pluripotent stem cells (iPSCs) that can be directed to differentiate to specific cell types. Trans-differentiation or direct reprogramming, on the other hand, involves the direct conversion of one cell type into another. In this review, we highlight how gene regulatory mechanisms identified to be critical for developmental processes were successfully used for cellular reprogramming of various cell types. We also discuss how the therapeutic use of the reprogrammed cells is beginning to revolutionize the field of regenerative medicine particularly in the repair and regeneration of damaged tissue and organs arising from pathological conditions or accidents. Lastly, we highlight some key challenges hindering the application of cellular reprogramming for therapeutic purposes.

scholarly journals Connectivity characterization of the mouse basolateral amygdalar complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Houri Hintiryan ◽  
Ian Bowman ◽  
David L. Johnson ◽  
Laura Korobkova ◽  
Muye Zhu ◽  
...  
Keyword(s):  
Granular Cell ◽  
Cell Types ◽  
Projection Neurons ◽  
Cell Type ◽  
Connectivity Map ◽  
Analysis Techniques ◽  
Domain Specific ◽  
Cell Type Specific ◽  
Unique Domain

AbstractThe basolateral amygdalar complex (BLA) is implicated in behaviors ranging from fear acquisition to addiction. Optogenetic methods have enabled the association of circuit-specific functions to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. Here, we apply machine-learning based computational and informatics analysis techniques to the results of circuit-tracing experiments to create a foundational, comprehensive BLA connectivity map. The analyses identify three distinct domains within the anterior BLA (BLAa) that house target-specific projection neurons with distinguishable morphological features. We identify brain-wide targets of projection neurons in the three BLAa domains, as well as in the posterior BLA, ventral BLA, posterior basomedial, and lateral amygdalar nuclei. Inputs to each nucleus also are identified via retrograde tracing. The data suggests that connectionally unique, domain-specific BLAa neurons are associated with distinct behavior networks.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals Histone modifications form a cell-type-specific chromosomal bar code that persists through the cell cycle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
John A. Halsall ◽  
Simon Andrews ◽  
Felix Krueger ◽  
Charlotte E. Rutledge ◽  
Gabriella Ficz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Histone Modifications ◽  
Expression Patterns ◽  
Cell Types ◽  
Cell Type ◽  
Bar Code ◽  
Genes Encoding ◽  
Cell Type Specific ◽  
Rolling Windows

AbstractChromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear. To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL), to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3. We show that chromosome regions (bands) of 10–50 Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1 and G2. They comprise 1–5 Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely. We found little change between cell cycle phases, whether compared by 5 Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains. Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription. In conclusion, modified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1 Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.

scholarly journals An analytical method for the identification of cell type-specific disease gene modules

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinting Guan ◽  
Yiping Lin ◽  
Yang Wang ◽  
Junchao Gao ◽  
Guoli Ji
Keyword(s):  
Disease Gene ◽  
Gene Interaction ◽  
Cell Types ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Disease ◽  
Cell Type Specific ◽  
Gene Modules ◽  
Disease Associated Genes

Abstract Background Genome-wide association studies have identified genetic variants associated with the risk of brain-related diseases, such as neurological and psychiatric disorders, while the causal variants and the specific vulnerable cell types are often needed to be studied. Many disease-associated genes are expressed in multiple cell types of human brains, while the pathologic variants affect primarily specific cell types. We hypothesize a model in which what determines the manifestation of a disease in a cell type is the presence of disease module comprised of disease-associated genes, instead of individual genes. Therefore, it is essential to identify the presence/absence of disease gene modules in cells. Methods To characterize the cell type-specificity of brain-related diseases, we construct human brain cell type-specific gene interaction networks integrating human brain nucleus gene expression data with a referenced tissue-specific gene interaction network. Then from the cell type-specific gene interaction networks, we identify significant cell type-specific disease gene modules by performing statistical tests. Results Between neurons and glia cells, the constructed cell type-specific gene networks and their gene functions are distinct. Then we identify cell type-specific disease gene modules associated with autism spectrum disorder and find that different gene modules are formed and distinct gene functions may be dysregulated in different cells. We also study the similarity and dissimilarity in cell type-specific disease gene modules among autism spectrum disorder, schizophrenia and bipolar disorder. The functions of neurons-specific disease gene modules are associated with synapse for all three diseases, while those in glia cells are different. To facilitate the use of our method, we develop an R package, CtsDGM, for the identification of cell type-specific disease gene modules. Conclusions The results support our hypothesis that a disease manifests itself in a cell type through forming a statistically significant disease gene module. The identification of cell type-specific disease gene modules can promote the development of more targeted biomarkers and treatments for the disease. Our method can be applied for depicting the cell type heterogeneity of a given disease, and also for studying the similarity and dissimilarity between different disorders, providing new insights into the molecular mechanisms underlying the pathogenesis and progression of diseases.

Cytoplasmic, nuclear, membrane-bound and secreted [35S]methionine-labelled polypeptide pattern in differentiating fibroblast stem cells in vitro

1989 ◽  
Vol 92 (2) ◽  
pp. 231-239
Author(s):  
P.I. Francz ◽  
K. Bayreuther ◽  
H.P. Rodemann
Keyword(s):  
Protein Fraction ◽  
Fibroblast Cell ◽  
Cell Types ◽  
Specific Marker ◽  
Human Skin Fibroblast ◽  
Nuclear Fraction ◽  
Cell Type ◽  
Marker Proteins ◽  
Cell Type Specific ◽  
Membrane Bound

Methods for the selective enrichment of various subpopulations of the human skin fibroblast cell line HH-8 have been developed. These methods permit the selection of homogeneous populations of the three mitotic fibroblast cell types MF I, II and III, and the four postmitotic cell types PMF IV, V, VI and VII. These seven cell types exhibit differentiation-dependent and cell-type-specific patterns of [35S]methionine-labelled polypeptides in total soluble cytoplasmic and nuclear proteins, also in membrane-bound proteins, and in secreted proteins. In the differentiation sequence MF II-MF III-PMF IV - PMF V - PMF VI 14 cell-type-specific marker proteins have been found in the cytoplasmic and nuclear fraction, also 24 cell-type-specific marker proteins have been found in the membrane-bound protein fraction, and 11 cell-type-specific marker proteins in the secreted protein fraction. Markers in spontaneously arising and experimentally selected or induced populations of a single fibroblast cell type were found to be identical.

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