scholarly journals Tissue-specific 5-hydroxymethylcytosine landscape of the human genome

2020 ◽  
Author(s):  
Bo He ◽  
Chao Zhang ◽  
Xiaoxue Zhang ◽  
Yu Fan ◽  
Hu Zeng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Genome Wide Association Study ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Epigenetic Mark ◽  
Human Tissues ◽  
Tissue Specific ◽  
Regulatory Functions

Abstract 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understand its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially hydroxymethylated regions (tsDhMRs), which are deposited in regulatory elements that regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription-factor-binding sites and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with SNPs identified by genome-wide association study (GWAS), linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific development and diseases.

scholarly journals Tissue-specific 5-hydroxymethylcytosine landscape of the human genome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo He ◽  
Chao Zhang ◽  
Xiaoxue Zhang ◽  
Yu Fan ◽  
Hu Zeng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Association Studies ◽  
Specific Gene ◽  
Epigenetic Mark ◽  
Genome Wide Association Studies ◽  
Human Tissues ◽  
Tissue Specific ◽  
Tissue Specific Gene ◽  
Specific Gene Expression

Abstract5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially-hydroxymethylated regions (tsDhMRs), which are deposited in regions that potentially regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription factors and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with single-nucleotide polymorphisms identified by genome-wide association studies and are linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific gene expression programs and functions.

Characterization of Tissue-Specific HIF-1 and HIF-2 Regulatory Elements of the Erythropoietin Gene

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4763-4763
Author(s):  
Donghoon Yoon ◽  
Hyojin Kim ◽  
Minyoung Jang ◽  
Jihyun Song ◽  
Gregory E Arnold ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Specific Binding ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Mrna Levels ◽  
Specific Element ◽  
Α Subunit ◽  
Tissue Specific

Abstract Hypoxia regulates erythropoiesis and other essential processes via hypoxia-inducible transcription factors (HIFs). HIFs are heterodimers that consist of an α subunit (3 isotypes with significant homology; HIF-1α, HIF-2α, HIF-3α), and a common b-subunit; HIF-1 and HIF-2, in some instances exhibiting tissue- and gene-specific gene regulation. Erythropoietin (EPO) was the first identified HIF-1 target gene with the defined HIF-1 binding sequence. However, subsequent works suggested that HIF-2 also regulates EPO transcription and that there are other regulatory elements of EPO gene (i.e. Kidney Inducible Element KIE, Negative Regulatory Element NRE, and Negative Regulatory Liver specific Element NRLE). In silico analysis of the human EPO genome found two additional potential HIF-binding elements in the KIE and NRE regions. The comparative analysis of phylogenically conserved sequences of human, mouse, dog, and rat Epo genes further refined these mouse Epo gene HIF-binding elements as mKIE, mNRE1, mNRE2, and mNRLE2. We treated mice in hypoxia chamber (8% O2) and monitored changes of Epo mRNA levels in liver, kidney, brain, spleen, and bone marrow. All tested tissues increased Epo transcription during hypoxia. Bone marrow, spleen, kidney, and brain showed a peak of induction of Epo transcript at 3 hours of hypoxia treatment, while liver reached the highest level at 6 hours. Mice were sacrificed and organs were harvested, and in vivo chromatin immunoprecipitation (ChIPs) was performed with antibodies against HIF-1α and HIF- 2α and tissue-specific binding regions were defined. The results from these studies are summarized below. HIF-1 mKIE rnNRE mNRE2 mNRLE2 Norm Hyp Norm Hyp Norm Hyp Norm Hyp Liver − + − − + − ? ? Kidney − + − − + − + − Brain − + − − − + − + BM − + − − − − − + Splsen − + − − − − − + HIF-2 mKIE mNRE mNRE2 mNRLE2 Norm Hyp Norm Hyp Norm Hyp Norm Hyp “+” denotes presence and “-” absence of binding of HIF-1 and HIF-2, “?” – indicates inconclusive results. “Norm” - normoxia, “Hyp” - hypoxia. Liver − + − − − + − + Kidney + − − − + − ? ? Brain − − − − − − − + BM − − − − − − + − Spleen − + − − − − − + In conclusion, we demonstrate the differential hypoxia-induced binding of HIF-1 and HIF-2 at different HIF binding elements in the tissues known to express Epo. Further studies will be required to define the function of these HIF-1 and HIF-2 binding elements in tissue specific Epo expression and their role in health and disease.

scholarly journals Tissue-specific profiling reveals distinctive regulatory architectures for ubiquitous, germline and somatic genes

2020 ◽  
Author(s):  
Jacques Serizay ◽  
Yan Dong ◽  
Jürgen Jänes ◽  
Michael Chesney ◽  
Chiara Cerrato ◽  
...  
Keyword(s):  
Gene Expression ◽  
Core Promoter ◽  
Regulatory Element ◽  
Expression Patterns ◽  
Somatic Tissue ◽  
Gene Expression Patterns ◽  
Specific Gene ◽  
Detailed Knowledge ◽  
Tissue Specific ◽  
C Elegans

AbstractDespite increasingly detailed knowledge of gene expression patterns, the regulatory architectures that drive them are not well understood. To address this, we compared transcriptional and regulatory element activities across five adult tissues of C. elegans, covering ∼90% of cells, and defined regulatory grammars associated with ubiquitous, germline and somatic tissue-specific gene expression patterns. We find architectural features that distinguish two major promoter types. Germline-specific and ubiquitously-active promoters have well positioned +1 and −1 nucleosomes associated with a periodic 10-bp WW signal. Somatic tissue-specific promoters lack these features, have wider nucleosome depleted regions, and are more enriched for core promoter elements, which surprisingly differ between tissues. A 10-bp periodic WW signal is also associated with +1 nucleosomes of ubiquitous promoters in fly and zebrafish but is not detected in mouse and human. Our results demonstrate fundamental differences in regulatory architectures of germline-active and somatic tissue-specific genes and provide a key resource for future studies.

scholarly journals SNPnotes: high-throughput tissue-specific functional annotation of single nucleotide variants

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1784
Author(s):  
Shraddha Pai ◽  
Michael J. Apostolides ◽  
Andrew Jung ◽  
Matthew A. Moss
Keyword(s):  
Gene Expression ◽  
Gene Mapping ◽  
High Throughput ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Tissue Specific ◽  
Functional Variants ◽  
Genome Regulation ◽  
Organ Systems ◽  
Variant Gene

A key challenge in the application of whole-genome sequencing (WGS) for clinical diagnostic and research is the high-throughput prioritization of functional variants in the non-coding genome. This challenge is compounded by context-specific genetic modulation of gene expression, and variant-gene mapping depends on the tissues and organ systems affected in a given disease; for instance, a disease affecting the gastrointestinal system would use maps specific to genome regulation in gut-related tissues. While there are large-scale atlases of genome regulation, such as GTEx and NIH Roadmap Epigenomics, the clinical genetics community lacks publicly-available stand-alone software for high-throughput annotation of custom variant data with user-defined tissue-specific epigenetic maps and clinical genetic databases, to prioritize variants for a specific biomedical application. In this work, we provide a simple software pipeline, called SNPnotes, which takes as input variant calls for a patient and prioritizes those using information on clinical relevance from ClinVar, tissue-specific gene regulation from GTEx and disease associations from the NHGRI-EBI GWAS catalogue. This pipeline was developed as part of SVAI Research's "Undiagnosed-1" event for collaborative patient diagnosis. We applied this pipeline to WGS-based variant calls for an individual with a history of gastrointestinal symptoms, using 12 gut-specific eQTL maps and GWAS associations for metabolic diseases, for variant-gene mapping. Out of 6,248,584 SNPs, the pipeline identified 151 high-priority variants, overlapping 129 genes. These top SNPs all have known clinical pathogenicity, modulate gene expression in gut tissues and have genetic associations with metabolic disorders, and serve as starting points for hypotheses about mechanisms driving clinical symptoms. Simple software changes can be made to customize the pipeline for other tissue-specific applications. Future extensions could integrate maps of tissue-specific regulatory elements, higher-order chromatin loops, and mutations affecting splice variants.

A modified pod specific promoter for high level heterologous expression of genes in legumes

2019 ◽  
Author(s):  
Aravind Kumar Konda ◽  
Pallavi Singh ◽  
Khela Ram Soren ◽  
Narendra Pratap Singh
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Specific Expression ◽  
Tissue Specific ◽  
Cis Acting ◽  
Inducible Promoters ◽  
Expression Of Genes ◽  
Enhanced Expression ◽  
High Level

Promoters are cis-acting regulatory elements that are usually present upstream to the coding sequences and determine the gene expression. Deployment of tissue specific and inducible promoters are constantly increasing for development of successful and stable multiple transgenic plants. To this end, as a strategy for enhanced expression of cis or transgenes, promoter engineering of the native msg promoter from soya bean has been carried out for executing pod specific expression of genes. Cis regulatory elements such as 5’UTR and poly (A) tract have been incorporated for imparting mRNA stability and translational enhancement to generate the modified 1.285 Kb pod specific promoter. Further to attain transcriptional enhancement the modified promoter has been cloned to generate Bi-directional Duplex Promoters (BDDP). The engineered msg promoter gene constructs can be deployed for high level tissue specific gene expression of cis/trans genes along with chosen terminator in chickpea. soybean and other legumes as well.

Epigenetics of Cellular Memory: Insights from the Chromatin Accessibility Landscape of the Mitotic Genome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4342-4342
Author(s):  
Chris C.S. Hsiung ◽  
Christapher Morrissey ◽  
Maheshi Udugama ◽  
Christopher Frank ◽  
Cheryl A. Keller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factors ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Dnase I ◽  
Specific Gene ◽  
Tissue Specific ◽  
Dnase I Sensitivity ◽  
Mitotic Chromatin

Abstract Normal development requires the coordination of cell cycle progression and gene expression to produce physiologically appropriate cell numbers of various lineages. The concomitant dysregulation of these two cellular programs is central to many malignant and non-malignant hematologic diseases, yet researchers still lack clear, general principles of how intrinsic properties of cell division could influence transcriptional regulation. Mitosis is a unique phase of the cell cycle that dramatically disrupts transcription: chromosomes condense to form microscopically recognizable structures, the nucleus is disassembled, RNA synthesis ceases, and the transcription machinery and many transcription factors are evicted from mitotic chromatin. How cells “remember” tissue-specific transcriptional programs through mitotic divisions remains largely unknown. Some transcription factors, including the erythroid master regulator, GATA1, and certain chromatin features are known to remain associated with DNA during mitosis. These molecular entities have been proposed to serve as mitotic “bookmarks” -- molecules that store gene regulatory information at individual loci through mitosis. However, we have limited knowledge of the composition, mechanism and function of mitotic bookmarks. In this context, chromatin structure deserves special consideration, as chromosome condensation during mitosis could potentially hinder transcription factor binding. To obtain the first genome-wide view of chromatin accessibility during mitosis, we mapped the DNase I sensitivity of the interphase versus mitotic genome in two maturation stages in a murine erythroblast cell line, G1E. Despite microscopic condensation of chromosomes during mitosis, we found that DNase I sensitivity is extensively preserved throughout the mappable genome, indicating that mitotic chromatin is not as condensed as commonly presumed. Individual genes and cis-regulatory elements can maintain all, part of, or none of its interphase accessibility during mitosis, demonstrating that accessibility of mitotic chromatin is locally specified. Promoters generally maintain accessibility during mitosis; moreover, promoters with the highest degree of accessibility preservation in mitosis in G1E cells tend to also be accessible across many murine tissues in interphase. In contrast to promoters, we found that enhancer accessibility is preferentially lost during mitosis, raising the possibility that memory of enhancer regulation may be altered during mitosis. Since enhancers play crucial roles in specifying tissue-specific gene expression patterns, we propose that this phase of the cell cycle may be especially susceptible to resetting of transcriptional programs. This hypothesis is supported by our preliminary results that revealed aberrant RNA polymerase II re-engagement with the genome and transcript production in early G1. Thus, mitosis could be a source of gene expression heterogeneity, with potential implications for cell fate transitions in proliferative cells, such as during stem cell lineage commitment, experimental reprogramming, and tumorigenesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals A sequence-based global map of regulatory activity for deciphering human genetics

2021 ◽  
Author(s):  
Kathleen M Chen ◽  
Aaron K Wong ◽  
Olga G Troyanskaya ◽  
Jian Zhou
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Human Genetics ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Sequence Information ◽  
Regulatory Activity ◽  
Tissue Specific ◽  
Regulatory Architecture ◽  
Sequence Class

Sequence is at the basis of how the genome shapes chromatin organization, regulates gene expression, and impacts traits and diseases. Epigenomic profiling efforts have enabled large-scale identification of regulatory elements, yet we still lack a sequence-based map to systematically identify regulatory activities from any sequence, which is necessary for predicting the effects of any variant on these activities. We address this challenge with Sei, a new framework for integrating human genetics data with sequence information to discover the regulatory basis of traits and diseases. Our framework systematically learns a vocabulary for the regulatory activities of sequences, which we call sequence classes, using a new deep learning model that predicts a compendium of 21,907 chromatin profiles across >1,300 cell lines and tissues, the most comprehensive to-date. Sequence classes allow for a global view of sequence and variant effects by quantifying diverse regulatory activities, such as loss or gain of cell-type-specific enhancer function. We show that sequence class predictions are supported by experimental data, including tissue-specific gene expression, expression QTLs, and evolutionary constraints based on population allele frequencies. Finally, we applied our framework to human genetics data. Sequence classes uniquely provide a non-overlapping partitioning of GWAS heritability by tissue-specific regulatory activity categories, which we use to characterize the regulatory architecture of 47 traits and diseases from UK Biobank. Furthermore, the predicted loss or gain of sequence class activities suggest specific mechanistic hypotheses for individual regulatory pathogenic mutations. We provide this framework as a resource to further elucidate the sequence basis of human health and disease.

scholarly journals Genome-Wide Histone Modifications and CTCF Enrichment Predict Gene Expression in Sheep Macrophages

2021 ◽  
Vol 11 ◽  
Author(s):  
Alisha T. Massa ◽  
Michelle R. Mousel ◽  
Maria K. Herndon ◽  
David R. Herndon ◽  
Brenda M. Murdoch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Modifications ◽  
Alveolar Macrophages ◽  
Immune Cell ◽  
Regulatory Elements ◽  
Chromatin Domain ◽  
Specific Gene ◽  
Topological Domains ◽  
Tissue Specific ◽  
Genome Wide

Alveolar macrophages function in innate and adaptive immunity, wound healing, and homeostasis in the lungs dependent on tissue-specific gene expression under epigenetic regulation. The functional diversity of tissue resident macrophages, despite their common myeloid lineage, highlights the need to study tissue-specific regulatory elements that control gene expression. Increasing evidence supports the hypothesis that subtle genetic changes alter sheep macrophage response to important production pathogens and zoonoses, for example, viruses like small ruminant lentiviruses and bacteria like Coxiella burnetii. Annotation of transcriptional regulatory elements will aid researchers in identifying genetic mutations of immunological consequence. Here we report the first genome-wide survey of regulatory elements in any sheep immune cell, utilizing alveolar macrophages. We assayed histone modifications and CTCF enrichment by chromatin immunoprecipitation with deep sequencing (ChIP-seq) in two sheep to determine cis-regulatory DNA elements and chromatin domain boundaries that control immunity-related gene expression. Histone modifications included H3K4me3 (denoting active promoters), H3K27ac (active enhancers), H3K4me1 (primed and distal enhancers), and H3K27me3 (broad silencers). In total, we identified 248,674 reproducible regulatory elements, which allowed assignment of putative biological function in macrophages to 12% of the sheep genome. Data exceeded the FAANG and ENCODE standards of 20 million and 45 million useable fragments for narrow and broad marks, respectively. Active elements showed consensus with RNA-seq data and were predictive of gene expression in alveolar macrophages from the publicly available Sheep Gene Expression Atlas. Silencer elements were not enriched for expressed genes, but rather for repressed developmental genes. CTCF enrichment enabled identification of 11,000 chromatin domains with mean size of 258 kb. To our knowledge, this is the first report to use immunoprecipitated CTCF to determine putative topological domains in sheep immune cells. Furthermore, these data will empower phenotype-associated mutation discovery since most causal variants are within regulatory elements.

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