scholarly journals Convergence of dispersed regulatory mutations predicts driver genes in prostate cancer

2016 ◽  
Author(s):  
Richard C. Sallari ◽  
Nicholas A. Sinnott-Armstrong ◽  
Juliet D. French ◽  
Ken J. Kron ◽  
Jason Ho ◽  
...  
Keyword(s):  
High Frequency ◽  
Three Dimensional ◽  
Low Frequency ◽  
Cell Type ◽  
Driver Genes ◽  
Normal Prostate ◽  
Regulatory Mutations ◽  
Cell Type Specific ◽  
Gene Regulatory ◽  
Upregulated Genes

ABSTRACTCancer sequencing predicts driver genes using recurrent protein-altering mutations, but detecting recurrence for non-coding mutations remains unsolved. Here, we present a convergence framework for recurrence analysis of non-coding mutations using three-dimensional co-localization of epigenomically-identified regions. We define the regulatory plexus of each gene as its cell-type-specific three-dimensional gene-regulatory neighborhood, inferred using Hi-C chromosomal interactions and chromatin state annotations. Using 16 matched tumor-normal prostate transcriptomes, we predict tumor-upregulated genes, and find enriched plexus mutations in distal regulatory regions normally repressed in prostate, suggesting out-of-context de-repression. Using 55 matched tumor-normal prostate genomes, we predict 15 driver genes by convergence of dispersed, low-frequency mutations into high-frequency dysregulation events along prostate-specific plexi, while controlling for mutational heterogeneity across regions, chromatin states, and patients. These putative drivers play roles in growth signaling, immune evasion, mitochondrial function, and vascularization, suggesting higher-order pathway-level convergence. We experimentally validate the PLCB4 plexus and its ability to affect the canonical PI3K cancer pathway.

scholarly journals The three-dimensional chromatin structure of the major human pancreatic cell types reveals lineage-specific regulatory architecture of T2D risk

2021 ◽  
Author(s):  
Su Chun ◽  
Long Gao ◽  
Catherine L May ◽  
James A Pippin ◽  
Keith Boehm ◽  
...  
Keyword(s):  
Single Cell ◽  
Target Genes ◽  
Genetic Diseases ◽  
Three Dimensional ◽  
Specific Gene ◽  
Cell Type ◽  
Pancreatic Cell ◽  
Regulatory Architecture ◽  
Cell Type Specific ◽  
Gene Regulatory

Three-dimensional (3D) chromatin organization maps help to dissect cell type-specific gene regulatory programs. Furthermore, 3D chromatin maps have contributed to elucidating the pathogenesis of complex genetic diseases by connecting distal regulatory regions and genetic risk variants to their respective target genes. To understand the cell type-specific regulatory architecture of diabetes risk, we generated transcriptomic and 3D epigenomic profiles of human pancreatic acinar, alpha, and beta cells using single-cell RNA-seq, single-cell ATAC-seq, and high-resolution Hi-C of sorted cells. Comparisons of these profiles revealed differential A/B (open/closed) chromatin compartmentalization, chromatin looping, and control of cell type-specific gene regulatory programs. We identified a total of 1,094 putative causal-variant-target-gene pairs at 129 type 2 diabetes GWAS signals using pancreatic 3D chromatin maps. We found that the connections between candidate causal variants and their putative target effector genes are cell-type stratified and emphasize previously underappreciated roles for alpha and acinar cells in diabetes pathogenesis

scholarly journals Caspase- and Serine Protease-dependent Apoptosis by the Death Domain of FADD in Normal Epithelial Cells

2003 ◽  
Vol 14 (1) ◽  
pp. 67-77 ◽  
Author(s):  
Jacqueline Thorburn ◽  
Laura M. Bender ◽  
Michael J. Morgan ◽  
Andrew Thorburn
Keyword(s):  
Epithelial Cells ◽  
Serine Protease ◽  
Death Domain ◽  
Cell Type ◽  
Normal Prostate ◽  
Effector Domain ◽  
Death Effector Domain ◽  
Prostate Epithelial Cells ◽  
Cell Type Specific ◽  
Death Effector

The adapter protein FADD consists of two protein interaction domains: a death domain and a death effector domain. The death domain binds to activated death receptors such as Fas, whereas the death effector domain binds to procaspase 8. An FADD mutant, which consists of only the death domain (FADD-DD), inhibits death receptor–induced apoptosis. FADD-DD can also activate a mechanistically distinct, cell type–specific apoptotic pathway that kills normal but not cancerous prostate epithelial cells. Here, we show that this apoptosis occurs through activation of caspases 9, 3, 6, and 7 and a serine protease. Simultaneous inhibition of caspases and serine proteases prevents FADD-DD–induced death. Inhibition of either pathway alone does not prevent cell death but does affect the morphology of the dying cells. Normal prostate epithelial cells require both the caspase and serine protease inhibitors to efficiently prevent apoptosis in response to TRAIL. In contrast, the serine protease inhibitor does not affect TRAIL-induced death in prostate tumor cells suggesting that the FADD-DD–dependent pathway can be activated by TRAIL. This apoptosis pathway is activated in a cell type–specific manner that is defective in cancer cells, suggesting that this pathway may be targeted during cancer development.

scholarly journals Timbre and Affect Dimensions: Evidence from Affect and Similarity Ratings and Acoustic Correlates of Isolated Instrument Sounds

2012 ◽  
Vol 30 (1) ◽  
pp. 49-70 ◽  
Author(s):  
Tuomas Eerola ◽  
Rafael Ferrer ◽  
Vinoo Alluri
Keyword(s):  
High Frequency ◽  
Sound Production ◽  
Three Dimensional ◽  
Low Frequency ◽  
Structural Features ◽  
Two Dimensions ◽  
Acoustic Features ◽  
Behavioral Experiments ◽  
Acoustic Correlates

considerable effort has been made towards understanding how acoustic and structural features contribute to emotional expression in music, but relatively little attention has been paid to the role of timbre in this process. Our aim was to investigate the role of timbre in the perception of affect dimensions in isolated musical sounds, by way of three behavioral experiments. In Experiment 1, participants evaluated perceived affects of 110 instrument sounds that were equal in duration, pitch, and dynamics using a three-dimensional affect model (valence, energy arousal, and tension arousal) and preference and emotional intensity. In Experiment 2, an emotional dissimilarity task was applied to a subset of the instrument sounds used in Experiment 1 to better reveal the underlying affect structure. In Experiment 3, the perceived affect dimensions as well as preference and intensity of a new set of 105 instrument sounds were rated by participants. These sounds were also uniform in pitch, duration, and playback dynamics but contained systematic manipulations in the dynamics of sound production, articulation, and ratio of high-frequency to low-frequency energy. The affect dimensions for all the experiments were then explained in terms of the three kinds of acoustic features extracted: spectral (e.g., ratio of high-frequency to low-frequency energy), temporal (e.g., attack slope), and spectro-temporal (e.g., spectral flux). High agreement among the participants' ratings across the experiments suggested that even isolated instrument sounds contain cues that indicate affective expression, and these are recognized as such by the listeners. A dominant portion (50-57%) of the two dimensions of affect (valence and energy arousal) could be predicted by linear combinations of few acoustic features such as ratio of high-frequency to low-frequency energy, attack slope, and spectral regularity. Links between these features and those observed in the vocal expression of affects and other sound phenomena are discussed.

Transcription Factor Binding Sites Are Genetic Determinant of Retroviral Integration in the Human Genome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 820-820
Author(s):  
Claudia Cattoglio ◽  
Barbara Felice ◽  
Davide Cittaro ◽  
Annarita Miccio ◽  
Giuliana Ferrari ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Site Selection ◽  
Binding Sites ◽  
High Frequency ◽  
Cell Type ◽  
Retroviral Integration ◽  
Target Site Selection ◽  
Integration Sites ◽  
Cell Type Specific ◽  
Genomic Regions

Abstract Gamma-retroviruses and lentiviruses integrate non-randomly in mammalian genomes, with specific preferences for active chromatin, promoters and regulatory regions. Gamma-retroviral gene transfer vectors show a high frequency of insertional gene activation, and may induce neoplastic or pre-neoplastic clonal expansions in patients treated with genetically modified cells. An analysis of >10,000 integration sites of a Moloney leukemia virus (MLV)-derived vector in human CD34+ hematopoietic progenitors showed that genes involved the control of growth, differentiation and development of the hematopoietic and immune system are targeted at high frequency and enriched in integration hot spots, suggesting that the cell gene expression program is instrumental in directing MLV integration. To investigate the role of transcriptional regulatory networks in retroviral target site selection, we analyzed the distribution of transcription factor binding sites (TFBSs) flanking >4,000 MLV- and HIV-derived proviruses in human hematopoietic and non-hematopoietic cells. We show that MLV vectors integrate in genomic regions enriched in cell-type specific subsets of TFBSs, independently from their relative position with respect to genes and transcription start sites. Conversely, HIV vectors appear to avoid TFBS-rich genomic regions. Hierarchical clustering and a principal component analysis of TFBSs flanking retroviral integration sites in CD34+ and HeLa cells showed that TFBS subsets are vector- and cell type-specific. Analysis of sequences flanking the integration sites of vectors carrying mutations in their long terminal repeats (LTRs), and of HIV vectors packaged with a MLV integrase, indicates that the MLV integrase and LTR enhancer are the viral determinants of the selection of TFBS-rich regions in the genome. Chromatin immunoprecipitation analysis shows that transcription factors bind the LTR enhancers in the cell nucleus before integration, and may therefore synergize with the integrase in tethering retroviral pre-integration complexes to transcriptionally active regulatory regions. This study identifies TFBSs as differential genomic determinants of retroviral target site selection in the human genome, and indicates that gamma-retroviruses and lentiviruses have evolved dramatically different strategies to interact with the host cell chromatin. These differences predict a higher risk in using gamma-retroviral vs. lentiviral vectors for human gene therapy applications, independently from the design of the vector and the transgene expression cassette.

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 Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the prenatal human hypothalamus

2021 ◽  
Author(s):  
Brian Herb ◽  
Hannah J Glover ◽  
Aparna Bhaduri ◽  
Alex M Casella ◽  
Tracy L Bale ◽  
...  
Keyword(s):  
Developmental Trajectories ◽  
Single Cells ◽  
Neuronal Diversity ◽  
Cell Type ◽  
Human Hypothalamus ◽  
Paired Samples ◽  
Cell Type Specific ◽  
Gene Regulatory ◽  
Stem Cell Populations ◽  
Temporal Trajectory

The hypothalamus is critically important for regulating most autonomic, metabolic, and behavioral functions essential for life and species propagation, yet a comprehensive understanding of neuronal subtypes and their development in the human brain is lacking. Here, we characterized the prenatal human hypothalamus by sequencing the transcriptomes of 45,574 single-cells from 12 embryos, spanning gestational weeks 4 through 25. These cells describe a temporal trajectory from proliferative stem cell populations to maturing neurons and glia, including 38 distinct excitatory and inhibitory neuronal subtypes. Merging these data with paired samples from the cortex and ganglionic eminences (GE) revealed two distinct neurogenesis pathways, one shared between GE and hypothalamus and a second unique to cortex. Gene regulatory network modeling predicted that these distinct maturation trajectories involve the activation of region- and cell type-specific transcription factor networks. These results provide the first comprehensive transcriptomic view of human hypothalamus development at cellular resolution.

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 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 State-dependent cell-type-specific membrane potential dynamics and unitary synaptic inputs in awake mice

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Aurélie Pala ◽  
Carl CH Petersen
Keyword(s):  
Membrane Potential ◽  
Barrel Cortex ◽  
Field Potential ◽  
Low Frequency ◽  
Inhibitory Neuron ◽  
Single Layer ◽  
Cell Type ◽  
State Dependent ◽  
Layer 2 ◽  
Cell Type Specific

The cellular and synaptic mechanisms driving cell-type-specific function during various cortical network activities and behaviors are poorly understood. Here, we targeted whole-cell recordings to two classes of inhibitory GABAergic neurons in layer 2/3 of the barrel cortex of awake head-restrained mice and correlated spontaneous membrane potential dynamics with cortical state and whisking behavior. Using optogenetic stimulation of single layer 2/3 excitatory neurons we measured unitary excitatory postsynaptic potentials (uEPSPs) across states. During active states, characterized by whisking and reduced low-frequency activity in the local field potential, parvalbumin-expressing neurons depolarized and, albeit in a small number of recordings, received uEPSPs with increased amplitude. In contrast, somatostatin-expressing neurons hyperpolarized and reduced firing rates during active states without consistent change in uEPSP amplitude. These results further our understanding of neocortical inhibitory neuron function in awake mice and are consistent with the hypothesis that distinct genetically-defined cell classes have different state-dependent patterns of activity.

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