scholarly journals Genetic and Epigenetic Features of Promoters with Ubiquitous Chromatin Accessibility Support Ubiquitous Transcription of Cell-essential Genes

2020 ◽  
Author(s):  
Kaili Fan ◽  
Jill E. Moore ◽  
Xiao-ou Zhang ◽  
Zhiping Weng
Keyword(s):  
Cell Types ◽  
Regulatory Elements ◽  
Mouse Cell ◽  
Chromatin Accessibility ◽  
Essential Genes ◽  
Chromatin State ◽  
Open Chromatin ◽  
High Turnover ◽  
Systematic Analysis ◽  
Encode Consortium

AbstractGene expression is controlled by regulatory elements with accessible chromatin. Although the majority of regulatory elements are cell type-specific, being in the open chromatin state in only one or a few cell types, approximately 16,000 regions in the human genome and 13,000 regions in the mouse genome are in the open chromatin state in nearly all of the 517 human and 94 mouse cell and tissue types assayed by the ENCODE consortium, respectively. We performed a systematic analysis on the subset of 9,000 human and 8,000 mouse ubiquitously (ubi) open chromatin regions that were also classified as candidate cis-regulatory elements (cCREs) with promoter-like signatures (PLSs) by the ENCODE consortium, which we refer to as ubi-PLSs. We found that these ubi-PLSs had higher levels of CG dinucleotides and corresponded to the genes with ubiquitously high levels of transcriptional activities. Furthermore, the transcription start sites of a vast majority of cell-essential genes are located in ubi-PLSs. ubi-PLSs are enriched in the motifs of ubiquitously expressed transcription factors and preferentially bound by transcriptional cofactors that regulate ubiquitously expressed genes. Finally, ubi-PLSs are highly conserved between human and mouse at the synteny level, but not as conserved at the sequence level, with a high turnover of transcription factor motif sites. Thus, there is a distinct set of roughly 9,000 promoters in the mammalian genome that are actively maintained in the open chromatin state in nearly all cell types to ensure the transcriptional program of cell-essential genes.

scholarly journals A Chromatin Accessibility Atlas of the Developing Human Telencephalon

2019 ◽  
Author(s):  
Eirene Markenscoff-Papadimitriou ◽  
Sean Whalen ◽  
Pawel Przytycki ◽  
Reuben Thomas ◽  
Fadya Binyameen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
De Novo ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Deep Layers ◽  
Health And Disease ◽  
Human Telencephalon

AbstractGene expression differs between cell types and regions within complex tissues such as the developing brain. To discover regulatory elements underlying this specificity, we generated genome-wide maps of chromatin accessibility in eleven anatomically-defined regions of the developing human telencephalon, including upper and deep layers of the prefrontal cortex. We predicted a subset of open chromatin regions (18%) that are most likely to be active enhancers, many of which are dynamic with 26% differing between early and late mid-gestation and 28% present in only one brain region. These region-specific predicted regulatory elements (pREs) are enriched proximal to genes with expression differences across regions and developmental stages and harbor distinct sequence motifs that suggest potential upstream regulators of regional and temporal transcription. We leverage this atlas to identify regulators of genes associated with autism spectrum disorder (ASD) including an enhancer of BCL11A, validated in mouse, and two functional de novo mutations in individuals with ASD in an enhancer of SLC6A1, validated in neuroblastoma cells. These applications demonstrate the utility of this atlas for decoding neurodevelopmental gene regulation in health and disease.SummaryTo discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from eleven dissected regions of the mid-gestation human telencephalon, including upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed regional differences in chromatin accessibility, including many specific to one brain region, and were correlated with gene expression differences across the same regions and gestational ages. pREs allowed us to map neurodevelopmental disorder risk genes to developing telencephalic regions, and we identified three functional de novo noncoding variants in pREs that alter enhancer function. In addition, transgenic experiments in mouse validated enhancer activity for a pRE proximal to BCL11A, showing how this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.

scholarly journals Long-range single-molecule mapping of chromatin accessibility in eukaryotes

2018 ◽  
Author(s):  
Zohar Shipony ◽  
Georgi K. Marinov ◽  
Matthew P. Swaffer ◽  
Nasa A. Sinott-Armstrong ◽  
Jan M. Skotheim ◽  
...  
Keyword(s):  
Single Molecule ◽  
Regulatory Elements ◽  
Dna Methyltransferases ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Open Chromatin ◽  
Structure Mapping ◽  
Long Read ◽  
Distal Regulatory Elements ◽  
Resolution Single

AbstractActive regulatory elements in eukaryotes are typically characterized by an open, nucleosome-depleted chromatin structure; mapping areas of open chromatin has accordingly emerged as a widely used tool in the arsenal of modern functional genomics. However, existing approaches for profiling chromatin accessibility are limited by their reliance on DNA fragmentation and short read sequencing, which leaves them unable to provide information about the state of chromatin on larger scales or reveal coordination between the chromatin state of individual distal regulatory elements. To address these limitations, we have developed a method for profiling accessibility of individual chromatin fibers at multi-kilobase length scale (SMAC-seq, or Single-Molecule long-read Accessible Chromatin mapping sequencing assay), enabling the simultaneous, high-resolution, single-molecule assessment of the chromatin state of distal genomic elements. Our strategy is based on combining the preferential methylation of open chromatin regions by DNA methyltransferases (CpG and GpC 5-methylcytosine (5mC) and N6-methyladenosine (m6A) enzymes) and the ability of long-read single-molecule nanopore sequencing to directly read out the methylation state of individual DNA bases. Applying SMAC-seq to the budding yeast Saccharomyces cerevisiae, we demonstrate that aggregate SMAC-seq signals match bulk-level accessibility measurements, observe single-molecule protection footprints of nucleosomes and transcription factors, and quantify the correlation between the chromatin states of distal genomic elements.

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.

scholarly journals Single cell epigenomic atlas of the developing human brain and organoids

2019 ◽  
Author(s):  
Ryan S. Ziffra ◽  
Chang N. Kim ◽  
Amy Wilfert ◽  
Tychele N. Turner ◽  
Maximilian Haeussler ◽  
...  
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Cell Fate ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Cell Type ◽  
Fate Specification ◽  
Cell Type Specific

AbstractDynamic changes in chromatin accessibility coincide with important aspects of neuronal differentiation, such as fate specification and arealization and confer cell type-specific associations to neurodevelopmental disorders. However, studies of the epigenomic landscape of the developing human brain have yet to be performed at single-cell resolution. Here, we profiled chromatin accessibility of >75,000 cells from eight distinct areas of developing human forebrain using single cell ATAC-seq (scATACseq). We identified thousands of loci that undergo extensive cell type-specific changes in accessibility during corticogenesis. Chromatin state profiling also reveals novel distinctions between neural progenitor cells from different cortical areas not seen in transcriptomic profiles and suggests a role for retinoic acid signaling in cortical arealization. Comparison of the cell type-specific chromatin landscape of cerebral organoids to primary developing cortex found that organoids establish broad cell type-specific enhancer accessibility patterns similar to the developing cortex, but lack many putative regulatory elements identified in homologous primary cell types. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.

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 In vivotissue-specific chromatin profiling inDrosophila melanogasterusing GFP-tagged nuclei

2021 ◽  
Author(s):  
Juan Jauregui-Lozano ◽  
Kimaya Bakhle ◽  
Vikki M. Weake
Keyword(s):  
Cell Types ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Specific Cell ◽  
Histone Marks ◽  
The Many ◽  
Chromatin Profiling ◽  
Photoreceptor Neurons ◽  
Multicellular Organisms

AbstractThe chromatin landscape defines cellular identity in multicellular organisms with unique patterns of DNA accessibility and histone marks decorating the genome of each cell type. Thus, profiling the chromatin state of different cell types in an intact organism under disease or physiological conditions can provide insight into how chromatin regulates cell homeostasisin vivo. To overcome the many challenges associated with characterizing chromatin state in specific cell types, we developed an improved approach to isolateDrosophilanuclei tagged with GFP expressed under Gal4/UAS control. Using this protocol, we profiled chromatin accessibility using Omni-ATAC, and examined the distribution of histone marks using ChIP-seq and CUT&Tag in adult photoreceptor neurons. We show that the chromatin landscape of photoreceptors reflects the transcriptional state of these cells, demonstrating the quality and reproducibility of our approach for profiling the transcriptome and epigenome of specific cell types inDrosophila.

scholarly journals N6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription

Science ◽  
2020 ◽  
Vol 367 (6477) ◽  
pp. 580-586 ◽  
Author(s):  
Jun Liu ◽  
Xiaoyang Dou ◽  
Chuanyuan Chen ◽  
Chuan Chen ◽  
Chang Liu ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Open Chromatin ◽  
Dependent Manner ◽  
Nuclear Exosome ◽  
Regulatory Rnas ◽  
Nuclear Degradation ◽  
Long Interspersed Element

N6-methyladenosine (m6A) regulates stability and translation of messenger RNA (mRNA) in various biological processes. In this work, we show that knockout of the m6A writer Mettl3 or the nuclear reader Ythdc1 in mouse embryonic stem cells increases chromatin accessibility and activates transcription in an m6A-dependent manner. We found that METTL3 deposits m6A modifications on chromosome-associated regulatory RNAs (carRNAs), including promoter-associated RNAs, enhancer RNAs, and repeat RNAs. YTHDC1 facilitates the decay of a subset of these m6A-modified RNAs, especially elements of the long interspersed element-1 family, through the nuclear exosome targeting–mediated nuclear degradation. Reducing m6A methylation by METTL3 depletion or site-specific m6A demethylation of selected carRNAs elevates the levels of carRNAs and promotes open chromatin state and downstream transcription. Collectively, our results reveal that m6A on carRNAs can globally tune chromatin state and transcription.

scholarly journals Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Matthias Thurner ◽  
Martijn van de Bunt ◽  
Jason M Torres ◽  
Anubha Mahajan ◽  
Vibe Nylander ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islet ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Human Islets ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Open Chromatin ◽  
Genome Wide Association Studies

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

scholarly journals Analysis of putative cis-regulatory elements regulating blood pressure variation

2020 ◽  
Vol 29 (11) ◽  
pp. 1922-1932
Author(s):  
Priyanka Nandakumar ◽  
Dongwon Lee ◽  
Thomas J Hoffmann ◽  
Georg B Ehret ◽  
Dan Arking ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Association Studies ◽  
Specific Effect ◽  
Cell Types ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Functional Scores ◽  
Cell Type Specific

Abstract Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of ‘expressed’ genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.

scholarly journals Analysis of putative cis-regulatory elements regulating blood pressure variation

2019 ◽  
Author(s):  
Priyanka Nandakumar ◽  
Dongwon Lee ◽  
Thomas J. Hoffmann ◽  
Georg B. Ehret ◽  
Dan Arking ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Pressure ◽  
Cell Types ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Functional Scores ◽  
Cell Type Specific ◽  
Different Tissues

AbstractHundreds of loci have been associated with blood pressure traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ∼100,000 Genetic Epidemiology Research on Aging (GERA) study participants. In the present study, we subsequently focused on determining putative regulatory regions for these and other tissues of relevance to blood pressure, to both fine-map these loci by pinpointing genes and variants of functional interest within them, and to identify any novel genes.We constructed maps of putative cis-regulatory elements using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Sequence variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. In order to identify genes of interest, we aggregate these variants in these putative cis-regulatory elements within 50Kb of the start or end of genes considered as “expressed” in these tissues or cell types using publicly available gene expression data, and use the deltaSVM scores as weights in the well-known group-wise sequence kernel association test (SKAT). We test for association with both blood pressure traits as well as expression within these tissues or cell types of interest, and identify several genes, including MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B, and PPCDC. Although our study centers on blood pressure traits, we additionally examined two known genes, SCN5A and NOS1AP involved in the cardiac trait QT interval, in the Atherosclerosis Risk in Communities Study (ARIC), as a positive control, and observed an expected heart-specific effect. Thus, our method may be used to identify variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.Author SummarySequence change in genes (“variants”) are linked to the presence and severity of different traits or diseases. However, as genes may be expressed in different tissues and at different times and degrees, using this information is expected to more accurately identify genes of interest. Variants within the genes are essential, but also in the sequences (“regulatory elements”) that control the genes’ expression in different tissues or cell types. In this study, we aim to use this information about expression and variants potentially involved in gene expression regulation to better pinpoint genes and variants in regulatory elements of interest for blood pressure regulation. We do so by taking advantage of such data that are publicly available, and use methods to combine information about variants in aggregate within a gene’s putative regulatory elements in tissues thought to be relevant for blood pressure, and identify several genes, meant to enable experimental follow-up.

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