scholarly journals Large organized chromatin lysine domains help distinguish primitive from differentiated cell populations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Seyed Ali Madani Tonekaboni ◽  
Benjamin Haibe-Kains ◽  
Mathieu Lupien
Keyword(s):  
Transposable Elements ◽  
Histone Modifications ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cell Populations ◽  
Genomic Features ◽  
Differentiated Cells ◽  
Chromatin Interactions ◽  
Topologically Associating Domains ◽  
Highly Expressed Genes

AbstractThe human genome is partitioned into a collection of genomic features, inclusive of genes, transposable elements, lamina interacting regions, early replicating control elements and cis-regulatory elements, such as promoters, enhancers, and anchors of chromatin interactions. Uneven distribution of these features within chromosomes gives rise to clusters, such as topologically associating domains (TADs), lamina-associated domains, clusters of cis-regulatory elements or large organized chromatin lysine (K) domains (LOCKs). Here we show that LOCKs from diverse histone modifications discriminate primitive from differentiated cell types. Active LOCKs (H3K4me1, H3K4me3 and H3K27ac) cover a higher fraction of the genome in primitive compared to differentiated cell types while repressive LOCKs (H3K9me3, H3K27me3 and H3K36me3) do not. Active LOCKs in differentiated cells lie proximal to highly expressed genes while active LOCKs in primitive cells tend to be bivalent. Genes proximal to bivalent LOCKs are minimally expressed in primitive cells. Furthermore, bivalent LOCKs populate TAD boundaries and are preferentially bound by regulators of chromatin interactions, including CTCF, RAD21 and ZNF143. Together, our results argue that LOCKs discriminate primitive from differentiated cell populations.

scholarly journals CREAM: Clustering of genomic REgions Analysis Method

2017 ◽  
Author(s):  
Seyed Ali Madani Tonekaboni ◽  
Parisa Mazrooei ◽  
Victor Kofia ◽  
Benjamin Haibe-Kains ◽  
Mathieu Lupien
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
R Package ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Analysis Method ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Highly Expressed Genes ◽  
Genomic Regions

ABSTRACTCellular identity relies on cell type-specific gene expression profiles controlled by cis-regulatory elements (CREs), such as promoters, enhancers and anchors of chromatin interactions. CREs are unevenly distributed across the genome, giving rise to distinct subsets such as individual CREs and Clusters Of cis-Regulatory Elements (COREs), also known as super-enhancers. Identifying COREs is a challenge due to technical and biological features that entail variability in the distribution of distances between CREs within a given dataset. To address this issue, we developed a new unsupervised machine learning approach termed Clustering of genomic REgions Analysis Method (CREAM) that outperforms the Ranking Of Super Enhancer (ROSE) approach. Specifically CREAM identified COREs are enriched in CREs strongly bound by master transcription factors according to ChIP-seq signal intensity, are proximal to highly expressed genes, are preferentially found near genes essential for cell growth and are more predictive of cell identity. Moreover, we show that CREAM enables subtyping primary prostate tumor samples according to their CORE distribution across the genome. We further show that COREs are enriched compared to individual CREs at TAD boundaries and these are preferentially bound by CTCF and factors of the cohesin complex (e.g.: RAD21 and SMC3). Finally, using CREAM against transcription factor ChIP-seq reveals CTCF and cohesin-specific COREs preferentially at TAD boundaries compared to intra-TADs. CREAM is available as an open source R package (https://CRAN.R-project.org/package=CREAM) to identify COREs from cis-regulatory annotation datasets from any biological samples.

scholarly journals The single-cell epigenetic regulatory landscape in mammalian perinatal testis development

2021 ◽  
Author(s):  
Jinyue Liao ◽  
Hoi Ching Suen ◽  
Shitao Rao ◽  
Alfred Chun Shui Luk ◽  
Ruoyu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Somatic Cells ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Cell Type

AbstractSpermatogenesis depends on an orchestrated series of developing events in germ cells and full maturation of the somatic microenvironment. To date, the majority of efforts to study cellular heterogeneity in testis has been focused on single-cell gene expression rather than the chromatin landscape shaping gene expression. To advance our understanding of the regulatory programs underlying testicular cell types, we analyzed single-cell chromatin accessibility profiles in more than 25,000 cells from mouse developing testis. We showed that scATAC-Seq allowed us to deconvolve distinct cell populations and identify cis-regulatory elements (CREs) underlying cell type specification. We identified sets of transcription factors associated with cell type-specific accessibility, revealing novel regulators of cell fate specification and maintenance. Pseudotime reconstruction revealed detailed regulatory dynamics coordinating the sequential developmental progressions of germ cells and somatic cells. This high-resolution data also revealed putative stem cells within the Sertoli and Leydig cell populations. Further, we defined candidate target cell types and genes of several GWAS signals, including those associated with testosterone levels and coronary artery disease. Collectively, our data provide a blueprint of the ‘regulon’ of the mouse male germline and supporting somatic cells.

scholarly journals Exploratory analysis of transposable elements expression in the C. elegans early embryo

2019 ◽  
Vol 20 (S9) ◽  
Author(s):  
Federico Ansaloni ◽  
Margherita Scarpato ◽  
Elia Di Schiavi ◽  
Stefano Gustincich ◽  
Remo Sanges
Keyword(s):  
Nervous System ◽  
Transposable Elements ◽  
Embryo Development ◽  
Cell Types ◽  
Early Embryo ◽  
Bioinformatics Pipeline ◽  
Early Embryo Development ◽  
C Elegans ◽  
Differentiated Cells ◽  
Different Cell Types

Abstract Background Transposable Elements (TE) are mobile sequences that make up large portions of eukaryote genomes. The functions they play within the complex cellular architecture are still not clearly understood, but it is becoming evident that TE have a role in several physiological and pathological processes. In particular, it has been shown that TE transcription is necessary for the correct development of mice embryos and that their expression is able to finely modulate transcription of coding and non-coding genes. Moreover, their activity in the central nervous system (CNS) and other tissues has been correlated with the creation of somatic mosaicisms and with pathologies such as neurodevelopmental and neurodegenerative diseases as well as cancers. Results We analyzed TE expression among different cell types of the Caenorhabditis elegans (C. elegans) early embryo asking if, where and when TE are expressed and whether their expression is correlated with genes playing a role in early embryo development. To answer these questions, we took advantage of a public C. elegans embryonic single-cell RNA-seq (sc-RNAseq) dataset and developed a bioinformatics pipeline able to quantify reads mapping specifically against TE, avoiding counting reads mapping on TE fragments embedded in coding/non-coding transcripts. Our results suggest that i) canonical TE expression analysis tools, which do not discard reads mapping on TE fragments embedded in annotated transcripts, may over-estimate TE expression levels, ii) Long Terminal Repeats (LTR) elements are mostly expressed in undifferentiated cells and might play a role in pluripotency maintenance and activation of the innate immune response, iii) non-LTR are expressed in differentiated cells, in particular in neurons and nervous system-associated tissues, and iv) DNA TE are homogenously expressed throughout the C. elegans early embryo development. Conclusions TE expression appears finely modulated in the C. elegans early embryo and different TE classes are expressed in different cell types and stages, suggesting that TE might play diverse functions during early embryo development.

scholarly journals Large-scale determination and characterization of cell type-specific regulatory elements in the human genome

2017 ◽  
Author(s):  
Can Wang ◽  
Shihua Zhang
Keyword(s):  
Histone Modifications ◽  
Large Scale ◽  
Chromatin Modification ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cell Type ◽  
Cell Identity ◽  
Functional Roles ◽  
Cancer Occurrence ◽  
Cell Type Specific

AbstractHistone modifications have been widely elucidated to play vital roles in gene regulation and cell identity. The Roadmap Epigenomics Consortium generated a reference catalogue of several key histone modifications across >100s of human cell types and tissues. Decoding these epigenomes into functional regulatory elements is a challenging task in computational biology. To this end, we adopted a differential chromatin modification analysis framework to comprehensively determine and characterize cell type-specific regulatory elements (CSREs) and their histone modification codes in the human epigenomes of five histone modifications across 127 tissues or cell types. The CSREs show significant relevance with cell type-specific biological functions and diseases and cell identity. Clustering of CSREs with their specificity signals reveals diverse histone codes, demonstrating the diversity of functional roles of CSREs within the same cell or tissue. Last but not least, dynamics of CSREs from close cell types or tissues can give a detailed view of developmental processes such as normal tissue development and cancer occurrence.

scholarly journals PIRCh-seq: functional classification of non-coding RNAs associated with distinct histone modifications

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jingwen Fang ◽  
Qing Ma ◽  
Ci Chu ◽  
Beibei Huang ◽  
Lingjie Li ◽  
...  
Keyword(s):  
Histone Modifications ◽  
Cell Types ◽  
Functional Classification ◽  
Chromatin Interactions ◽  
Specific Manner ◽  
Comprehensive Survey ◽  
Allele Specific ◽  
Non Coding Rnas ◽  
Nascent Transcripts

AbstractWe develop PIRCh-seq, a method which enables a comprehensive survey of chromatin-associated RNAs in a histone modification-specific manner. We identify hundreds of chromatin-associated RNAs in several cell types with substantially less contamination by nascent transcripts. Non-coding RNAs are found enriched on chromatin and are classified into functional groups based on the patterns of their association with specific histone modifications. We find single-stranded RNA bases are more chromatin-associated, and we discover hundreds of allele-specific RNA-chromatin interactions. These results provide a unique resource to globally study the functions of chromatin-associated lncRNAs and elucidate the basic mechanisms of chromatin-RNA interactions.

scholarly journals Intra- and inter-chromosomal chromatin interactions mediate genetic effects on regulatory networks

2017 ◽  
Author(s):  
O. Delaneau ◽  
M. Zazhytska ◽  
C. Borel ◽  
C. Howald ◽  
S. Kumar ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Cell Types ◽  
Regulatory Elements ◽  
Regulatory Domains ◽  
Regulatory Variants ◽  
Chromatin Interactions ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Cell Type Specific ◽  
Cis And Trans

SummaryGenome-wide studies on the genetic basis of gene expression and the structural properties of chromatin have considerably advanced our understanding of the function of the human genome. However, it remains unclear how structure relates to function and, in this work, we aim at bridging both by assembling a dataset that combines the activity of regulatory elements (e.g. enhancers and promoters), expression of genes and genetic variations of 317 individuals and across two cell types. We show that the regulatory activity is structured within 12,583 Cis Regulatory Domains (CRDs) that are cell type specific and highly reflective of the local (i.e. Topologically Associating Domains) and global (i.e. A/B nuclear compartments) nuclear organization of the chromatin. These CRDs essentially delimit the sets of active regulatory elements involved in the transcription of most genes, thereby capturing complex regulatory networks in which the effects of regulatory variants are propagated and combined to finally mediate expression Quantitative Trait Loci. Overall, our analysis reveals the complexity and specificity of cis and trans regulatory networks and their perturbation by genetic variation.

scholarly journals Stable unmethylated DNA demarcates expressed genes and their cis-regulatory space in plant genomes

2020 ◽  
Vol 117 (38) ◽  
pp. 23991-24000 ◽  
Author(s):  
Peter A. Crisp ◽  
Alexandre P. Marand ◽  
Jaclyn M. Noshay ◽  
Peng Zhou ◽  
Zefu Lu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Developmental Stages ◽  
Chromatin Modification ◽  
Leaf Tissue ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Functional Genes ◽  
Specific Cell ◽  
Chromatin Interactions

The genomic sequences of crops continue to be produced at a frenetic pace. It remains challenging to develop complete annotations of functional genes and regulatory elements in these genomes. Chromatin accessibility assays enable discovery of functional elements; however, to uncover the full portfolio of cis-elements would require profiling of many combinations of cell types, tissues, developmental stages, and environments. Here, we explore the potential to use DNA methylation profiles to develop more complete annotations. Using leaf tissue in maize, we define ∼100,000 unmethylated regions (UMRs) that account for 5.8% of the genome; 33,375 UMRs are found greater than 2 kb from genes. UMRs are highly stable in multiple vegetative tissues, and they capture the vast majority of accessible chromatin regions from leaf tissue. However, many UMRs are not accessible in leaf, and these represent regions with potential to become accessible in specific cell types or developmental stages. These UMRs often occur near genes that are expressed in other tissues and are enriched for binding sites of transcription factors. The leaf-inaccessible UMRs exhibit unique chromatin modification patterns and are enriched for chromatin interactions with nearby genes. The total UMR space in four additional monocots ranges from 80 to 120 megabases, which is remarkably similar considering the range in genome size of 271 megabases to 4.8 gigabases. In summary, based on the profile from a single tissue, DNA methylation signatures provide powerful filters to distill large genomes down to the small fraction of putative functional genes and regulatory elements.

scholarly journals Diverse epithelial cell populations contribute to the regeneration of secretory units in injured salivary glands

Development ◽  
2020 ◽  
Vol 147 (19) ◽  
pp. dev192807
Author(s):  
Ninche Ninche ◽  
Mingyu Kwak ◽  
Soosan Ghazizadeh
Keyword(s):  
Salivary Glands ◽  
De Novo ◽  
Cell Types ◽  
Myoepithelial Cells ◽  
Lineage Tracing ◽  
Secretory Cells ◽  
Cell Populations ◽  
Cellular Plasticity ◽  
Ductal Cells ◽  
Differentiated Cells

ABSTRACTSalivary glands exert exocrine secretory function to provide saliva for lubrication and protection of the oral cavity. Its epithelium consists of several differentiated cell types, including acinar, ductal and myoepithelial cells, that are maintained in a lineage-restricted manner during homeostasis or after mild injuries. Glandular regeneration following a near complete loss of secretory cells, however, may involve cellular plasticity, although the mechanism and extent of such plasticity remain unclear. Here, by combining lineage-tracing experiments with a model of severe glandular injury in the mouse submandibular gland, we show that de novo formation of acini involves induction of cellular plasticity in multiple non-acinar cell populations. Fate-mapping analysis revealed that, although ductal stem cells marked by cytokeratin K14 and Axin2 undergo a multipotency switch, they do not make a significant contribution to acinar regeneration. Intriguingly, more than 80% of regenerated acini derive from differentiated cells, including myoepithelial and ductal cells, that appear to dedifferentiate to a progenitor-like state before re-differentiation into acinar cells. The potential of diverse cell populations serving as a reserve source for acini widens the therapeutic options for hyposalivation.

scholarly journals The Nuclear Lamina as an Organizer of Chromosome Architecture

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 136 ◽  
Author(s):  
Yuri Y. Shevelyov ◽  
Sergey V. Ulianov
Keyword(s):  
Gene Expression ◽  
Interphase Nucleus ◽  
Spatial Organization ◽  
Nuclear Lamina ◽  
Cell Types ◽  
Embryonic Cells ◽  
Chromosome Architecture ◽  
Differentiated Cells ◽  
Chromatin Interactions ◽  
Associated Proteins

The nuclear lamina (NL) is a meshwork of lamins and lamin-associated proteins adjoining the inner side of the nuclear envelope. In early embryonic cells, the NL mainly suppresses background transcription, whereas, in differentiated cell types, its disruption affects gene expression more severely. Normally, the NL serves as a backbone for multiple chromatin anchoring sites, thus shaping the spatial organization of chromosomes in the interphase nucleus. However, upon cell senescence, aging, or in some types of terminally differentiated cells and lamin-associated diseases, the loss of NL-chromatin tethering causes drastic alterations in chromosome architecture. Here, we provide an overview of the recent advances in the field of NL-chromatin interactions, focusing on their impact on chromatin positioning, compaction, repression, and spatial organization.

scholarly journals Conservation of transcription factor binding specificities across 600 million years of bilateria evolution

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Kazuhiro R Nitta ◽  
Arttu Jolma ◽  
Yimeng Yin ◽  
Ekaterina Morgunova ◽  
Teemu Kivioja ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Specificity ◽  
Cell Types ◽  
Regulatory Elements ◽  
Relative Importance ◽  
Specific Expression ◽  
Differentiated Cells ◽  
In Cis ◽  
Human And Mouse

Divergent morphology of species has largely been ascribed to genetic differences in the tissue-specific expression of proteins, which could be achieved by divergence in cis-regulatory elements or by altering the binding specificity of transcription factors (TFs). The relative importance of the latter has been difficult to assess, as previous systematic analyses of TF binding specificity have been performed using different methods in different species. To address this, we determined the binding specificities of 242 Drosophila TFs, and compared them to human and mouse data. This analysis revealed that TF binding specificities are highly conserved between Drosophila and mammals, and that for orthologous TFs, the similarity extends even to the level of very subtle dinucleotide binding preferences. The few human TFs with divergent specificities function in cell types not found in fruit flies, suggesting that evolution of TF specificities contributes to emergence of novel types of differentiated cells.

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