scholarly journals Evaluation of Chromatin Accessibility in Prefrontal Cortex of Schizophrenia Cases and Controls

2017 ◽  
Author(s):  
Julien Bryois ◽  
Melanie E Garrett ◽  
Lingyun Song ◽  
Alexias Safi ◽  
Paola Giusti-Rodriguez ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Disease Risk ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Brain Diseases ◽  
Open Chromatin ◽  
Regulatory Processes ◽  
Fold Enrichment ◽  
Genomic Studies

AbstractSchizophrenia genome-wide association (GWA) studies have identified over 150 regions of the genome that are associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in brain are highly enriched for SNP-heritability for schizophrenia (10.6 fold enrichment, P=2.4×10−4, second only to genomic regions conserved in Eutherian mammals) and replicated in an independent dataset (9.0 fold enrichment, P=2.7×10−4). This degree of enrichment of schizophrenia heritability was higher than in open chromatin found in 138 different cell and tissue types. Brain open chromatin regions that overlapped highly conserved regions exhibited an even higher degree of heritability enrichment, indicating that conservation can identify functional subsets within regulatory elements active in brain. However, we did not identify chromatin accessibility differences between schizophrenia cases and controls, nor did we find an interaction of chromatin QTLs with case-control status. This indicates that although causal variants map within regulatory elements, mechanisms other than differential chromatin may govern the contribution of regulatory element variation to schizophrenia risk. Our results strongly implicate gene regulatory processes involving open chromatin in the pathogenesis of schizophrenia, and suggest a strategy to understand the hundreds of common variants emerging from large genomic studies of complex brain diseases.

scholarly journals Genome-wide annotation of gene regulatory elements linked to cell fitness

2021 ◽  
Author(s):  
Tyler S. Klann ◽  
Alejandro Barrera ◽  
Adarsh R. Ettyreddy ◽  
Ryan A. Rickels ◽  
Julien Bryois ◽  
...  
Keyword(s):  
Target Genes ◽  
Disease Risk ◽  
Regulatory Element ◽  
Cancer Cell Line ◽  
K562 Cells ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Cell Type Specificity ◽  
Cellular Processes ◽  
Genome Wide

AbstractNoncoding regulatory elements control gene expression and govern all biological processes. Epigenomic profiling assays have identified millions of putative regulatory elements, but systematically determining the function of each of those regulatory elements remains a substantial challenge. Here we adapt CRISPR-dCas9-based epigenomic regulatory element screening (CERES) technology to screen all >100,000 putative non-coding regulatory elements defined by open chromatin sites in human K562 leukemia cells for their role in regulating essential cellular processes. In an initial screen containing more than 1 million gRNAs, we discovered approximately 12,000 regulatory elements with evidence of impact on cell fitness. We validated many of the screen hits in K562 cells, evaluated cell-type specificity in a second cancer cell line, and identified target genes of regulatory elements using CERES perturbations combined with single cell RNA-seq. This comprehensive and quantitative genome-wide map of essential regulatory elements represents a framework for extensive characterization of noncoding regulatory elements that drive complex cell phenotypes and for prioritizing non-coding genetic variants that likely contribute to common traits and disease risk.

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 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 SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guojun Hou ◽  
Isaac T. W. Harley ◽  
Xiaoming Lu ◽  
Tian Zhou ◽  
Ning Xu ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Immune Cell ◽  
Disease Risk ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Type I ◽  
Distal Enhancer ◽  
Disease Etiology ◽  
Risk Variant ◽  
Protective Allele

AbstractSince most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter. NF-kB binds the disease protective allele in a sequence-specific manner, increasing expression of this immunoregulatory microRNA. Finally, CRISPR activation-based modulation of this enhancer in the PBMCs of SLE patients attenuates type I interferon pathway activation by increasing miR-146a expression. Our work provides a strategy to define non-coding RNA functional regulatory elements using disease-associated variants and provides mechanistic links between autoimmune disease risk genetic variation and disease etiology.

scholarly journals Dynamics of Cardiomyocyte Transcriptome and Chromatin Landscape Demarcates Key Events of Heart Development

2018 ◽  
Author(s):  
Michal Pawlak ◽  
Katarzyna Z. Kedzierska ◽  
Maciej Migdal ◽  
Karim Abu Nahia ◽  
Jordan A. Ramilowski ◽  
...  
Keyword(s):  
Heart Development ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Proximal Promoter ◽  
Global Changes ◽  
Open Chromatin ◽  
Sequence Motifs ◽  
Loss Of Function ◽  
Heart Looping

ABSTRACTThe development of an organ involves dynamic regulation of gene transcription and complex multipathway interactions. To better understand transcriptional regulatory mechanism driving heart development and the consequences of its disruption, we isolated cardiomyocytes (CMs) from wild-type zebrafish embryos at 24, 48 and 72 hours post fertilization corresponding to heart looping, chamber formation and heart maturation, and from mutant lines carrying loss-of-function mutations in gata5, tbx5a and hand2, transcription factors (TFs) required for proper heart development. The integration of CM transcriptomics (RNA-seq) and genome-wide chromatin accessibility maps (ATAC-seq) unravelled dynamic regulatory networks driving crucial events of heart development. These networks contained key cardiac TFs including Gata5/6, Nkx2.5, Tbx5/20, and Hand2, and are associated with open chromatin regions enriched for DNA sequence motifs belonging to the family of the corresponding TFs. These networks were disrupted in cardiac TF mutants, indicating their importance in proper heart development. The most prominent gene expression changes, which correlated with chromatin accessibility modifications within their proximal promoter regions, occurred between heart looping and chamber formation, and were associated with metabolic and hematopoietic/cardiac switch during CM maturation. Furthermore, loss of function of cardiac TFs Gata5, Tbx5a, and Hand2 affected the cardiac regulatory networks and caused global changes in chromatin accessibility profile. Among regions with differential chromatin accessibility in mutants were highly conserved non-coding elements which represent putative cis regulatory elements with potential role in heart development and disease. Altogether, our results revealed the dynamic regulatory landscape at key stages of heart development and identified molecular drivers of heart morphogenesis.

scholarly journals ECOA-7. Conserved cell-lineage controlled chromatin accessibility in human and mouse glioblastoma stem cells predicts functionally distinct subgroups

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii2-ii2
Author(s):  
Xi Lu ◽  
Naga Prathyusha Maturi ◽  
Malin Jarvius ◽  
Linxuan Zhao ◽  
Yuan Xie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epigenetic Regulation ◽  
Regulatory Element ◽  
Cell Lineage ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cell Of Origin ◽  
Glioblastoma Stem Cells ◽  
Transcription Factor Motif ◽  
Accessible Chromatin

Abstract There is ample support for developmental control of glioblastoma stem cells (GSCs), and a deeper knowledge of their epigenetic regulation could be central to more efficient glioblastoma (GBM) therapies. For this purpose, we analyzed the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered an epigenetic variability of both mouse and human GSC cultures that differed from transcriptome clusters. Both mouse and human chromatin accessibility-guided clusters were predominantly determined by distal regulatory elements, displayed unique sets of transcription factor motif enrichment, and exhibited different functional and drug-response properties. Cross-species analysis of distal regulatory element regions in accessible chromatin of mouse and human cultures revealed conserved epigenetic regulation of GSCs.

scholarly journals Chromatin accessibility analysis uncovers regulatory element landscape in prostate cancer progression

2020 ◽  
Author(s):  
Joonas Uusi-Mäkelä ◽  
Ebrahim Afyounian ◽  
Francesco Tabaro ◽  
Tomi Häkkinen ◽  
Alessandro Lussana ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Progression ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Prostate Cancer Progression ◽  
Accessibility Analysis ◽  
A Genome

AbstractAberrant oncogene functions and structural variation alter the chromatin structure in cancer cells. While gene regulation by chromatin states has been studied extensively, chromatin accessibility and its relevance in aberrant gene expression during prostate cancer progression is not well understood. Here, we report a genome-wide chromatin accessibility analysis of clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration-resistant prostate cancer (CRPC) and integrative analysis with transcriptome, methylome, and proteome profiles of the same samples to uncover disease-relevant regulatory elements and their association to altered gene expression during prostate cancer progression. While promoter accessibility is consistent during disease initiation and progression, at distal sites chromatin accessibility is variable enabling transcription factors (TFs) binding patterns that are differently activated in different patients and disease stages. We identify consistent progression-related chromatin alterations during the progression to CRPC. By studying the TF binding patterns, we demonstrate the activation and suppression of androgen receptor-driven regulatory programs during PC progression and identify complementary TF regulatory modules characterized by e.g. MYC and glucocorticoid receptor. By correlation analysis we assign at least one putative regulatory region for 62% of genes and 85% of proteins differentially expressed during prostate cancer progression. Taken together, our analysis of the chromatin landscape in PC identifies putative regulatory elements for the majority of cancer-associated genes and characterizes their impact on the cancer phenotype.

scholarly journals Hepatic-Specific Accessibility of Igf1 Gene Enhancers Is Independent of Growth Hormone Signaling

2013 ◽  
Vol 27 (12) ◽  
pp. 2080-2092 ◽  
Author(s):  
Mahalakshmi Santhanam ◽  
Dennis J. Chia
Keyword(s):  
Gene Regulation ◽  
Gene Transcription ◽  
Tissue Expression ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Binding Motifs ◽  
Tissue Specific ◽  
Regulatory Domains ◽  
Binding Domains

The diverse roles of IGF-1 in physiology include acting as the endocrine intermediate to elicit the anabolic actions of GH. The majority of serum IGF-1 is synthesized in liver, where GH stimulates Igf1 gene transcription via the transcription factor, signal transducer and activator of transcription (Stat)5b. We and others have identified multiple Stat5-binding domains at the Igf1 locus that function in gene regulation, but it remains unclear whether the roles of these domains are tissue specific. Survey of the chromatin landscape of regulatory domains can provide insight about mechanisms of gene regulation, with chromatin accessibility regarded as a hallmark feature of regulatory domains. We prepared chromatin from liver, kidney, and spleen of C57BL/6 mice, and used formaldehyde-associated isolation of regulatory elements to assess chromatin accessibility at the major Igf1 promoter and 7 -binding enhancers. Whereas the promoters of other prototypical tissue-specific genes are open in a tissue-specific way, the major Igf1 promoter is open in all 3 tissues, albeit moderately more so in liver. In contrast, chromatin accessibility at Igf1 Stat5-binding domains is essentially restricted to liver, indicating that the enhancers are driving extensive differences in tissue expression. Furthermore, studies with Ghrhrlit/lit mice reveal that prior GH exposure is not necessary to establish open chromatin at these domains. Lastly, formaldehyde-associated isolation of regulatory elements of human liver samples confirms open chromatin at IGF1 Promoter 1, but unexpectedly, homologous Stat5-binding motifs are not accessible. We conclude that robust GH-stimulated hepatic Igf1 gene transcription utilizes tissue-specific mechanisms of epigenetic regulation that are established independent of GH signaling.

scholarly journals Functional genomics in autoimmune diseases

2020 ◽  
Vol 29 (R1) ◽  
pp. R59-R65
Author(s):  
James Ding ◽  
Antonios Frantzeskos ◽  
Gisela Orozco
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Functional Genomics ◽  
Disease Risk ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Disease Etiology ◽  
Significant Research ◽  
Highly Correlated

Abstract Associations between genetic loci and increased susceptibility to autoimmune disease have been well characterized, however, translating this knowledge into mechanistic insight and patient benefit remains a challenge. While improvements in the precision, completeness and accuracy of our genetic understanding of autoimmune diseases will undoubtedly be helpful, meeting this challenge will require two interlinked problems to be addressed: first which of the highly correlated variants at an individual locus is responsible for increased disease risk, and second what are the downstream effects of this variant. Given that the majority of loci are thought to affect non-coding regulatory elements, the second question is often reframed as what are the target gene(s) and pathways affected by causal variants. Currently, these questions are being addressed using a wide variety of novel techniques and datasets. In many cases, these approaches are complementary and it is likely that the most accurate picture will be generated by consolidating information relating to transcription, regulatory activity, chromatin accessibility, chromatin conformation and readouts from functional experiments, such as genome editing and reporter assays. It is clear that it will be necessary to gather this information from disease relevant cell types and conditions and that by doing so our understanding of disease etiology will be improved. This review is focused on the field of autoimmune disease functional genomics with a particular focus on the most exciting and significant research to be published within the last couple of years.

scholarly journals A comparative analysis of chromatin accessibility in cattle, pig, and mouse tissues

2020 ◽  
Author(s):  
Michelle M Halstead ◽  
Colin Kern ◽  
Perot Saelao ◽  
Ying Wang ◽  
Ganrea Chanthavixay ◽  
...  
Keyword(s):  
Agricultural Research ◽  
Rapid Evolution ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Model Organisms ◽  
Individual Species ◽  
Open Chromatin ◽  
Tissue Specific ◽  
Mouse Tissues ◽  
Intergenic Regions

AbstractBackgroundAlthough considerable progress has been made towards annotating the noncoding portion of the human and mouse genomes, regulatory elements in other species, such as livestock, remain poorly characterized. This lack of functional annotation poses a substantial roadblock to agricultural research and diminishes the value of these species as model organisms. As active regulatory elements are typically characterized by chromatin accessibility, we implemented the Assay for Transposase Accessible Chromatin (ATAC-seq) to annotate and characterize regulatory elements in pigs and cattle, given a set of eight adult tissues.ResultsOverall, 306,304 and 273,594 active regulatory elements were identified in pig and cattle, respectively. 71,478 porcine and 47,454 bovine regulatory elements were highly tissue-specific and were correspondingly enriched for binding motifs of known tissue-specific transcription factors. However, in every tissue the most prevalent accessible motif corresponded to the insulator CTCF, suggesting pervasive involvement in 3-D chromatin organization. Taking advantage of a similar dataset in mouse, open chromatin in pig, cattle, and mice were compared, revealing that the conservation of regulatory elements, in terms of sequence identity and accessibility, was consistent with evolutionary distance; whereas pig and cattle shared about 20% of accessible sites, mice and ungulates only had about 10% of accessible sites in common. Furthermore, conservation of accessibility was more prevalent at promoters than at intergenic regions.ConclusionsThe lack of conserved accessibility at distal elements is consistent with rapid evolution of enhancers, and further emphasizes the need to annotate regulatory elements in individual species, rather than inferring elements based on homology. This atlas of chromatin accessibility in cattle and pig constitutes a substantial step towards annotating livestock genomes and dissecting the regulatory link between genome and phenome.

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