scholarly journals Evolution of the embryonic cis-regulatory landscapes between divergent Phallusia and Ciona ascidians.

2018 ◽  
Author(s):  
Alicia Madgwick ◽  
Marta Silvia Magri ◽  
Christelle Dantec ◽  
Damien Gailly ◽  
Ulla-Maj Fiuza ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Expression Patterns ◽  
Sequence Divergence ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Genes ◽  
Open Chromatin ◽  
Regulatory Sequences ◽  
Last Common Ancestor ◽  
Approximate Distance

Ascidian species of the Phallusia and Ciona genera are distantly related, their last common ancestor dating several hundred million years ago. Although their genome sequences have extensively diverged since this radiation, Phallusia and Ciona species share almost identical early morphogenesis and stereotyped cell lineages. Here, we explored the evolution of transcriptional control between P. mammillata and C. robusta. We combined genome-wide mapping of open chromatin regions in both species with a comparative analysis of the regulatory sequences of a test set of 10 pairs of orthologous early regulatory genes with conserved expression patterns. We find that ascidian chromatin accessibility landscapes obey similar rules as in other metazoa. Open-chromatin regions are short, highly conserved within each genus and cluster around regulatory genes. The dynamics of chromatin accessibility and closest-gene expression are strongly correlated during early embryogenesis. Open-chromatin regions are highly enriched in cis-regulatory elements: 73% of 49 open chromatin regions around our test genes behaved as either distal enhancers or proximal enhancer/promoters following electroporation in Phallusia eggs. Analysis of this datasets suggests a pervasive use in ascidians of shadow enhancers with partially overlapping activities. Cross-species electroporations point to a deep conservation of both the trans-regulatory logic between these distantly-related ascidians and the cis-regulatory activities of individual enhancers. Finally, we found that the relative order and approximate distance to the transcription start site of open chromatin regions can be conserved between Ciona and Phallusia species despite extensive sequence divergence, a property that can be used to identify orthologous enhancers, whose regulatory activity can partially diverge.

scholarly journals A cell atlas of chromatin accessibility across 25 adult human tissues

2021 ◽  
Author(s):  
Kai Zhang ◽  
James D. Hocker ◽  
Michael Miller ◽  
Xiaomeng Hou ◽  
Joshua Chiou ◽  
...  
Keyword(s):  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Regulatory Sequences ◽  
Cell Type ◽  
Organ Systems ◽  
The Status ◽  
Gene Regulatory ◽  
Multiple Donors

SUMMARYCurrent catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of human gene regulatory elements in diverse cell types and tissues in the human body, we applied single cell chromatin accessibility assays to 25 distinct human tissue types from multiple donors. The resulting chromatin maps comprising ∼500,000 nuclei revealed the status of open chromatin for over 750,000 candidate cis-regulatory elements (cCREs) in 54 distinct cell types. We further delineated cell type-specific and tissue-context dependent gene regulatory programs, and developmental stage specificity by comparing with a recent human fetal chromatin accessibility atlas. We finally used these chromatin maps to interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues and organ systems.

A Global Vista of the Epigenomic State of the Mouse Submandibular Gland

2021 ◽  
pp. 002203452110120
Author(s):  
C. Gluck ◽  
S. Min ◽  
A. Oyelakin ◽  
M. Che ◽  
E. Horeth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Expression Patterns ◽  
Global Gene Expression ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Submandibular Salivary Gland ◽  
Data Sets ◽  
Control Mechanisms ◽  
Chromatin Immunoprecipitation Sequencing

The parotid, submandibular, and sublingual glands represent a trio of oral secretory glands whose primary function is to produce saliva, facilitate digestion of food, provide protection against microbes, and maintain oral health. While recent studies have begun to shed light on the global gene expression patterns and profiles of salivary glands, particularly those of mice, relatively little is known about the location and identity of transcriptional control elements. Here we have established the epigenomic landscape of the mouse submandibular salivary gland (SMG) by performing chromatin immunoprecipitation sequencing experiments for 4 key histone marks. Our analysis of the comprehensive SMG data sets and comparisons with those from other adult organs have identified critical enhancers and super-enhancers of the mouse SMG. By further integrating these findings with complementary RNA-sequencing based gene expression data, we have unearthed a number of molecular regulators such as members of the Fox family of transcription factors that are enriched and likely to be functionally relevant for SMG biology. Overall, our studies provide a powerful atlas of cis-regulatory elements that can be leveraged for better understanding the transcriptional control mechanisms of the mouse SMG, discovery of novel genetic switches, and modulating tissue-specific gene expression in a targeted fashion.

scholarly journals EPCO-31. EPIGENOMIC INTRATUMORAL HETEROGENEITY OF GLIOBLASTOMA IN THREE-DIMENSIONAL SPACE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii76-ii76
Author(s):  
Radhika Mathur ◽  
Sriranga Iyyanki ◽  
Stephanie Hilz ◽  
Chibo Hong ◽  
Joanna Phillips ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Spatial Location ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Intratumoral Heterogeneity ◽  
Tumor Evolution ◽  
Open Chromatin

Abstract Treatment failure in glioblastoma is often attributed to intratumoral heterogeneity (ITH), which fosters tumor evolution and generation of therapy-resistant clones. While ITH in glioblastoma has been well-characterized at the genomic and transcriptomic levels, the extent of ITH at the epigenomic level and its biological and clinical significance are not well understood. In collaboration with neurosurgeons, neuropathologists, and biomedical imaging experts, we have established a novel topographical approach towards characterizing epigenomic ITH in three-dimensional (3-D) space. We utilize pre-operative MRI scans to define tumor volume and then utilize 3-D surgical neuro-navigation to intra-operatively acquire 10+ samples representing maximal anatomical diversity. The precise spatial location of each sample is mapped by 3-D coordinates, enabling tumors to be visualized in 360-degrees and providing unprecedented insight into their spatial organization and patterning. For each sample, we conduct assay for transposase-accessible chromatin using sequencing (ATAC-Seq), which provides information on the genomic locations of open chromatin, DNA-binding proteins, and individual nucleosomes at nucleotide resolution. We additionally conduct whole-exome sequencing and RNA sequencing for each spatially mapped sample. Integrative analysis of these datasets reveals distinct patterns of chromatin accessibility within glioblastoma tumors, as well as their associations with genetically defined clonal expansions. Our analysis further reveals how differences in chromatin accessibility within tumors reflect underlying transcription factor activity at gene regulatory elements, including both promoters and enhancers, and drive expression of particular gene expression sets, including neuronal and immune programs. Collectively, this work provides the most comprehensive characterization of epigenomic ITH to date, establishing its importance for driving tumor evolution and therapy resistance in glioblastoma. As a resource for further investigation, we have provided our datasets on an interactive data sharing platform – The 3D Glioma Atlas – that enables 360-degree visualization of both genomic and epigenomic ITH.

scholarly journals Comprehensive analysis of single cell ATAC-seq data with SnapATAC

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rongxin Fang ◽  
Sebastian Preissl ◽  
Yang Li ◽  
Xiaomeng Hou ◽  
Jacinta Lucero ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Cell Analysis ◽  
Expression Patterns ◽  
Regulatory Elements ◽  
Cellular Heterogeneity ◽  
Specific Gene ◽  
Open Chromatin ◽  
Cell Type ◽  
Process Data ◽  
Cell Type Specific

AbstractIdentification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by sample heterogeneity. Single cell analysis of accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volume of data pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC dissects cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC is applied to 55,592 single-nucleus ATAC-seq profiles from the mouse secondary motor cortex. The analysis reveals ~370,000 candidate regulatory elements in 31 distinct cell populations in this brain region and inferred candidate cell-type specific transcriptional regulators.

P-element-mediated enhancer detection applied to the study of oogenesis in Drosophila

Development ◽  
1989 ◽  
Vol 107 (2) ◽  
pp. 189-200 ◽  
Author(s):  
U. Grossniklaus ◽  
H.J. Bellen ◽  
C. Wilson ◽  
W.J. Gehring
Keyword(s):  
Germ Line ◽  
Expression Patterns ◽  
Cell Types ◽  
Regulatory Elements ◽  
P Element ◽  
Regulatory Sequences ◽  
Transcriptional Regulatory ◽  
Morphological Criteria ◽  
Enhancer Detection ◽  
New Strategies

We have stained the ovaries of nearly 600 different Drosophila strains carrying single copies of a P-element enhancer detector. This transposon detects neighbouring genomic transcriptional regulatory sequences by means of a beta-galactosidase reporter gene. Numerous strains are stained in specific cells and at specific stages of oogenesis and provide useful ovarian markers for cell types that in some cases have not previously been recognized by morphological criteria. Since recent data have suggested that a substantial number of the regulatory elements detected by enhancer detection control neighbouring genes, we discuss the implications of our results concerning ovarian gene expression patterns in Drosophila. We have also identified a small number of insertion-linked recessive mutants that are sterile or lead to ovarian defects. We observe a strong correlation with specific germ line staining patterns in these strains, suggesting that certain patterns are more likely to be associated with female sterile genes than others. On the basis of our results, we suggest new strategies, which are not primarily based on the generation of mutants, to screen for and isolated female sterile genes.

Regulatory elements in the 5'-flanking region and the first intron contribute to transcriptional control of the mouse alpha 1 type I collagen gene

1989 ◽  
Vol 9 (5) ◽  
pp. 2224-2227
Author(s):  
R A Rippe ◽  
S I Lorenzen ◽  
D A Brenner ◽  
M Breindl
Keyword(s):  
Transcriptional Control ◽  
Type I Collagen ◽  
Regulatory Elements ◽  
Regulatory Sequences ◽  
Type I ◽  
Col1a1 Gene ◽  
First Intron ◽  
Flanking Region ◽  
Specific Regulation ◽  
High Level

We have identified two blocks of regulatory sequences located in the 5'-flanking region and the first intron of the mouse alpha 1 type I collagen (COL1A1) gene. Both blocks were found to contain positive as well as negative regulatory elements. Sequences located within 222 base pairs upstream of the transcription start site showed a strong stimulatory effect on the COL1A1 promoter and were sufficient for tissue-specific regulation of the COL1A1 gene. The combined upstream and intron regulatory sequences showed a marked inhibition of COL1A1 promoter activity in fibroblasts. This finding suggests that additional, more remote regulatory sequences may be required for establishing the high level of activity of the endogenous COL1A1 gene in fibroblastoid cells.

scholarly journals Bmp2 Transcription in Osteoblast Progenitors Is Regulated by a Distant 3′ Enhancer Located 156.3 Kilobases from the Promoter

2007 ◽  
Vol 27 (8) ◽  
pp. 2934-2951 ◽  
Author(s):  
Ronald L. Chandler ◽  
Kelly J. Chandler ◽  
Karen A. McFarland ◽  
Douglas P. Mortlock
Keyword(s):  
Risk Factor ◽  
Osteoblast Differentiation ◽  
Expression Patterns ◽  
Artificial Chromosome ◽  
Regulatory Elements ◽  
Bone Morphogenetic Protein 2 ◽  
Regulatory Function ◽  
Regulatory Sequences ◽  
Bac Clone ◽  
Osteoblast Progenitor

ABSTRACT Bone morphogenetic protein 2 (encoded by Bmp2) has been implicated as an important signaling ligand for osteoblast differentiation and bone formation and as a genetic risk factor for osteoporosis. To initially survey a large genomic region flanking the mouse Bmp2 gene for cis-regulatory function, two bacterial artificial chromosome (BAC) clones that extend far upstream and downstream of the gene were engineered to contain a lacZ reporter cassette and tested in transgenic mice. Each BAC clone directs a distinct subset of normal Bmp2 expression patterns, suggesting a modular arrangement of distant Bmp2 regulatory elements. Strikingly, regulatory sequences required for Bmp2 expression in differentiating osteoblasts, as well as tooth buds, hair placodes, kidney, and other tissues, are located more than 53 kilobases 3′ to the promoter. By testing BACs with engineered deletions across this distant 3′ region, we parsed these regulatory elements into separate locations and more closely refined the location of the osteoblast progenitor element. Finally, a conserved osteoblast progenitor enhancer was identified within a 656-bp sequence located 156.3 kilobases 3′ from the promoter. The identification of this enhancer should permit further investigation of upstream regulatory mechanisms that control Bmp2 transcription during osteoblast differentiation and are relevant to further studies of Bmp2 as a candidate risk factor gene for osteoporosis.

scholarly journals Enhanced TF binding site maps improve regulatory networks learned from accessible chromatin data

2019 ◽  
Author(s):  
Shubhada R. Kulkarni ◽  
D. Marc Jones ◽  
Klaas Vandepoele
Keyword(s):  
Binding Site ◽  
Dna Sequences ◽  
Regulatory Networks ◽  
Transcriptional Control ◽  
Chromatin Accessibility ◽  
Systematic Evaluation ◽  
Open Chromatin ◽  
Ensemble Approach ◽  
Complete Cell ◽  
Regulatory Dna

ABSTRACTDetermining where transcription factors (TF) bind in genomes provides insights into which transcriptional programs are active across organs, tissue types, and environmental conditions. Recent advances in high-throughput profiling of regulatory DNA have yielded large amounts of information about chromatin accessibility. Interpreting the functional significance of these datasets requires knowledge of which regulators are likely to bind these regions. This can be achieved by using information about TF binding preferences, or motifs, to identify TF binding events that are likely to be functional. Although different approaches exist to map motifs to DNA sequences, a systematic evaluation of these tools in plants is missing. Here we compare four motif mapping tools widely used in the Arabidopsis research community and evaluate their performance using chromatin immunoprecipitation datasets for 40 TFs. Downstream gene regulatory network (GRN) reconstruction was found to be sensitive to the motif mapper used. We further show that the low recall of FIMO, one of the most frequently used motif mapping tools, can be overcome by using an Ensemble approach, which combines results from different mapping tools. Several examples are provided demonstrating how the Ensemble approach extends our view on transcriptional control for TFs active in different biological processes. Finally, a new protocol is presented to efficiently derive more complete cell type-specific GRNs through the integrative analysis of open chromatin regions, known binding site information, and expression datasets.

scholarly journals Chromatin accessibility and regulatory vocabulary across indicine cattle tissues

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Pâmela A. Alexandre ◽  
Marina Naval-Sánchez ◽  
Moira Menzies ◽  
Loan T. Nguyen ◽  
Laercio R. Porto-Neto ◽  
...  
Keyword(s):  
Motif Discovery ◽  
Target Genes ◽  
Developmental Stages ◽  
Bos Taurus ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Model Organisms ◽  
Open Chromatin ◽  
Health And Disease ◽  
Collaborative Efforts

Abstract Background Spatiotemporal changes in the chromatin accessibility landscape are essential to cell differentiation, development, health, and disease. The quest of identifying regulatory elements in open chromatin regions across different tissues and developmental stages is led by large international collaborative efforts mostly focusing on model organisms, such as ENCODE. Recently, the Functional Annotation of Animal Genomes (FAANG) has been established to unravel the regulatory elements in non-model organisms, including cattle. Now, we can transition from prediction to validation by experimentally identifying the regulatory elements in tropical indicine cattle. The identification of regulatory elements, their annotation and comparison with the taurine counterpart, holds high promise to link regulatory regions to adaptability traits and improve animal productivity and welfare. Results We generate open chromatin profiles for liver, muscle, and hypothalamus of indicine cattle through ATAC-seq. Using robust methods for motif discovery, motif enrichment and transcription factor binding sites, we identify potential master regulators of the epigenomic profile in these three tissues, namely HNF4, MEF2, and SOX factors, respectively. Integration with transcriptomic data allows us to confirm some of their target genes. Finally, by comparing our results with Bos taurus data we identify potential indicine-specific open chromatin regions and overlaps with indicine selective sweeps. Conclusions Our findings provide insights into the identification and analysis of regulatory elements in non-model organisms, the evolution of regulatory elements within two cattle subspecies as well as having an immediate impact on the animal genetics community in particular for a relevant productive species such as tropical cattle.

scholarly journals Comparative chromatin accessibility upon BDNF-induced neuronal activity delineates neuronal regulatory elements

2021 ◽  
Author(s):  
Ignacio L. Ibarra ◽  
Vikram S. Ratnu ◽  
Lucia Gordillo ◽  
In-Young Hwang ◽  
Luca Mariani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Synaptic Plasticity ◽  
Neuronal Activity ◽  
Cortical Neurons ◽  
Complex Traits ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Control ◽  
Comparative Genomic ◽  
Regulatory Sequences

Neuronal activity induced by brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences decreased BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal activity.

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