scholarly journals Joint inference and alignment of genome structures enables characterization of compartment-independent reorganization across cell types

2019 ◽  
Author(s):  
Lila Rieber ◽  
Shaun Mahony
Keyword(s):  
Nuclear Periphery ◽  
Cell Types ◽  
Cell Type ◽  
Specific Chromosome ◽  
Chromosome Conformation ◽  
Histone Marks ◽  
Joint Inference ◽  
Differential Gene Regulation ◽  
Main Driver ◽  
Cell Type Specific

AbstractCell-type-specific chromosome conformation is correlated with differential gene regulation. Broad compartmentalization into two compartments (A & B) is proposed to be the main driver of cell-specific chromosome organization. However it is unclear what fraction of chromosome conformation changes between cell types and conditions is independent of changes in compartmentalization and whether any such compartment-independent reorganization is functionally important. We developed MultiMDS to jointly infer and align 3D chromosomal structures, thereby enabling a quantitative comparison of locus-specific changes across Hi-C datasets. We compared Hi-C datasets from yeast, which lack compartmentalization, grown with and without galactose. These comparisons confirmed known relocalizations as well as identifying additional examples. We also compared mammalian datasets across a variety of cell lines. We found a consistent enrichment for changes along the A/B compartment (nuclear interior/nuclear periphery) axis, even when comparing the same cell type from different individuals. Despite the prevalence of compartment changes, we consistently find compartment-independent relocalizations of loci that are within the A compartment in both compared cell types. Some such intra-compartment relocalizations involve loci that display enhancer-associated histone marks in one cell type and polycomb-associated histone marks in the other. MultiMDS thus enables a new way to compare chromosome conformations across two Hi-C datasets.Availabilityhttps://github.com/seqcode/multimds

scholarly journals Joint inference and alignment of genome structures enables characterization of compartment-independent reorganization across cell types

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Lila Rieber ◽  
Shaun Mahony
Keyword(s):  
K562 Cells ◽  
Cell Types ◽  
Data Sets ◽  
Cell Type ◽  
Histone Marks ◽  
Joint Inference ◽  
3D Localization ◽  
Topologically Associated Domains ◽  
Cell Type Specific

Abstract Background Comparisons of Hi–C data sets between cell types and conditions have revealed differences in topologically associated domains (TADs) and A/B compartmentalization, which are correlated with differences in gene regulation. However, previous comparisons have focused on known forms of 3D organization while potentially neglecting other functionally relevant differences. We aimed to create a method to quantify all locus-specific differences between two Hi–C data sets. Results We developed MultiMDS to jointly infer and align 3D chromosomal structures from two Hi–C data sets, thereby enabling a new way to comprehensively quantify relocalization of genomic loci between cell types. We demonstrate this approach by comparing Hi–C data across a variety of cell types. We consistently find relocalization of loci with minimal difference in A/B compartment score. For example, we identify compartment-independent relocalizations between GM12878 and K562 cells that involve loci displaying enhancer-associated histone marks in one cell type and polycomb-associated histone marks in the other. Conclusions MultiMDS is the first tool to identify all loci that relocalize between two Hi–C data sets. Our method can identify 3D localization differences that are correlated with cell-type-specific regulatory activities and which cannot be identified using other methods.

scholarly journals Accurate imputation of histone modifications using transcription

2020 ◽  
Author(s):  
Zhong Wang ◽  
Alexandra G. Chivu ◽  
Lauren A. Choate ◽  
Edward J. Rice ◽  
Donald C. Miller ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Active Chromatin ◽  
Histone Marks ◽  
Repressive Mark ◽  
Cell Type Specific ◽  
The Relationship ◽  
Machine Learning Tool

AbstractWe trained a sensitive machine learning tool to infer the distribution of histone marks using maps of nascent transcription. Transcription captured the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. The relationship between active histone marks and transcription was conserved in all cell types examined, allowing individual labs to annotate active functional elements in mammals with similar richness as major consortia. Using imputation as an interpretative tool uncovered cell-type specific differences in how the PRC2-dependent repressive mark, H3K27me3, corresponds to transcription, and revealed that transcription initiation requires both chromatin accessibility and an active chromatin environment demonstrating that initiation is less promiscuous than previously thought.

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 An atlas of lamina-associated chromatin across thirteen human cell types reveals cell-type-specific and multiple subtypes of peripheral heterochromatin

2020 ◽  
Author(s):  
Kathleen C. Keough ◽  
Parisha P. Shah ◽  
Nadeera M. Wickramasinghe ◽  
Carolyn E. Dundes ◽  
Angela Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Cell ◽  
Regulation Of Gene Expression ◽  
Nuclear Periphery ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Type Specific ◽  
Cellular Identity ◽  
Peripheral Heterochromatin

AbstractThree-dimensional genome organization, specifically organization of heterochromatin at the nuclear periphery, coordinates cell type-specific gene regulation. While defining various histone modifications and chromatin-associated proteins in multiple cell types has provided important insights into epigenetic regulation of gene expression and cellular identity, peripheral heterochromatin has not been mapped comprehensively and relatively few examples have emerged detailing the role of peripheral heterochromatin in cellular identity, cell fate choices, and/or organogenesis. In this study, we define nuclear peripheral heterochromatin organization signatures based on association with LAMIN B1 and/or dimethylation of lysine 9 on H3 (H3K9me2) across thirteen human cell types encompassing pluripotent stem cells, intermediate progenitors and differentiated cells from all three germ layers. Genomic analyses across this atlas reveal that lamin-associated chromatin is organized into at least two different compartments, defined by differences in genome coverage, chromatin accessibility, residence of transposable elements, replication timing domains, and gene complements. Our datasets reveal that only a small subset of lamin-associated chromatin domains are cell type invariant, underscoring the complexity of peripheral heterochromatin organization. Moreover, by integrating peripheral chromatin maps with transcriptional data, we find evidence of cooperative shifts between chromatin structure and gene expression associated with each cell type. This atlas of peripheral chromatin provides the largest resource to date for peripheral chromatin organization and a deeper appreciation for how this organization may impact the establishment and maintenance of cellular identity.

scholarly journals High Resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells

2019 ◽  
Author(s):  
Peiyao A. Zhao ◽  
Takayo Sasaki ◽  
David M. Gilbert
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
Embryonic Stem ◽  
Replication Timing ◽  
Cell Types ◽  
S Phase ◽  
List Type ◽  
Cell Type ◽  
Histone Marks ◽  
Cell Type Specific

ABSTRACTDNA replication in mammalian cells occurs in a defined temporal order during S phase, known as the replication timing (RT) programme. RT is developmentally regulated and correlated with chromatin conformation and local transcriptional potential. Here we present RT profiles of unprecedented temporal resolution in two human embryonic stem cell lines, human colon carcinoma line HCT116 as well as F1 subspecies hybrid mouse embryonic stem cells and their neural progenitor derivatives. Strong enrichment of nascent DNA in fine temporal windows reveals a remarkable degree of cell to cell conservation in replication timing and patterns of replication genome-wide. We identify 5 patterns of replication in all cell types, consistent with varying degrees of initiation efficiency. Zones of replication initiation were found throughout S phase and resolved to ~50kb precision. Temporal transition regions were resolved into segments of uni-directional replication punctuated with small zones of inefficient initiation. Small and large valleys of convergent replication were consistent with either termination or broadly distributed initiation, respectively. RT correlated with chromatin compartment across all cell types but correlations of initiation time to chromatin domain boundaries and histone marks were cell type specific. Haplotype phasing revealed previously unappreciated regions of allele-specific and alleleindependent asynchronous replication. Allele-independent asynchrony was associated with large transcribed genes that resemble common fragile sites. Altogether, these data reveal a remarkably deterministic temporal choreography of DNA replication in mammalian cells.Highly homogeneous replication landscape between cells in a populationInitiation zones resolved within constant timing and timing transition regionsActive histone marks enriched within early initiation zones while enrichment of repressive marks is cell type specific.Transcribed long genes replicate asynchronously.

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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