scholarly journals Defining Regulatory Elements in the Human Genome Using Nucleosome Occupancy and Methylome Sequencing (NOMe-Seq)

2018 ◽  
pp. 209-229 ◽  
Author(s):  
Suhn Kyong Rhie ◽  
Shannon Schreiner ◽  
Peggy J. Farnham
Keyword(s):  
Human Genome ◽  
Nucleosome Occupancy ◽  
Regulatory Elements

scholarly journals Haplotype-aware single-cell multiomics uncovers functional effects of somatic structural variation

2021 ◽  
Author(s):  
Hyobin Jeong ◽  
Karen Grimes ◽  
Peter-Martin Bruch ◽  
Tobias Rausch ◽  
Patrick Hasenfeld ◽  
...  
Keyword(s):  
Single Cell ◽  
Nucleosome Occupancy ◽  
Single Cells ◽  
Chromosomal Rearrangements ◽  
Regulatory Elements ◽  
Computational Method ◽  
Tumour Heterogeneity ◽  
Cancer Genomes ◽  
Functional Consequences ◽  
Oncogenic Transcription Factor

Somatic structural variants (SVs) are widespread in cancer genomes, however, their impact on tumorigenesis and intra-tumour heterogeneity is incompletely understood, since methods to functionally characterize the broad spectrum of SVs arising in cancerous single-cells are lacking. We present a computational method, scNOVA, that couples SV discovery with nucleosome occupancy analysis by haplotype-resolved single-cell sequencing, to systematically uncover SV effects on cis-regulatory elements and gene activity. Application to leukemias and cell lines uncovered SV outcomes at several loci, including dysregulated cancer-related pathways and mono-allelic oncogene expression near SV breakpoints. At the intra-patient level, we identified different yet overlapping subclonal SVs that converge on aberrant Wnt signaling. We also deconvoluted the effects of catastrophic chromosomal rearrangements resulting in oncogenic transcription factor dysregulation. scNOVA directly links SVs to their functional consequences, opening the door for single-cell multiomics of SVs in heterogeneous cell populations.

scholarly journals High-throughput identification of long-range regulatory elements and their target promoters in the human genome

2013 ◽  
Vol 41 (9) ◽  
pp. 4835-4846 ◽  
Author(s):  
Yih-Chii Hwang ◽  
Qi Zheng ◽  
Brian D. Gregory ◽  
Li-San Wang
Keyword(s):  
Human Genome ◽  
Long Range ◽  
High Throughput ◽  
Regulatory Elements ◽  
Target Promoters

scholarly journals A heterochromatic histone methyltransferase lowers nucleosome occupancy at euchromatic promoters

2018 ◽  
Author(s):  
H.M. Chen ◽  
T.B. Sackton ◽  
B. Mutlu ◽  
J. Wang ◽  
S. Keppler-Ross ◽  
...  
Keyword(s):  
Nucleosome Occupancy ◽  
Histone H3 ◽  
Nuclear Lamina ◽  
Regulatory Elements ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
C Elegans ◽  
Muscle Gene Expression ◽  
Chromatin Configuration ◽  
Muscle Gene

AbstractH3K9me3 (histone H3 modified with tri-methylation at lysine 9) is a hallmark of transcriptional silencing and heterochromatin. However, its global effects on the genome, including euchromatin, are less well understood. Here we develop Formaldehyde-Assisted Identification of Regulatory Elements (FAIRE) for C. elegans to examine the chromatin configuration of mutants that lack virtually all H3K9me3, while leaving H3K9me1 and H3K9me2 intact. We find that nucleosomes are mildly disrupted, and levels of H3K9me2 and H3K27me3 rise in mutant embryos. In addition to these expected changes, the most dramatic change occurs in euchromatin: many regions encompassing transcription start sites (TSSs) gain an average of two nucleosomes in mutants. The affected regions normally lack H3K9me3, revealing a locus non-autonomous role for H3K9me3. Affected TSSs are associated with genes that are active in epithelia and muscles, and implicated in development, locomotion, morphogenesis and transcription. Mutant embryos develop normally under ideal laboratory conditions but die when challenged, with defects in morphogenesis and development. Our findings reveal that H3K9me3 protects transcription start sites within euchromatin from nucleosome deposition. These results may be relevant to mammals, where diseases that disrupt the nuclear lamina and heterochromatin can alter epithelial and muscle gene expression.

scholarly journals Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Simon M. Hoser ◽  
Anne Hoffmann ◽  
Andreas Meindl ◽  
Maximilian Gamper ◽  
Jörg Fallmann ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Human Genome ◽  
Splice Site ◽  
Mutational Analysis ◽  
Mitochondrial Protein ◽  
Regulatory Elements ◽  
Trna Genes ◽  
Mitochondrial Trna ◽  
Mobility Shift ◽  
Cloverleaf Structure

Abstract Background The presence of nuclear mitochondrial DNA (numtDNA) has been reported within several nuclear genomes. Next to mitochondrial protein-coding genes, numtDNA sequences also encode for mitochondrial tRNA genes. However, the biological roles of numtDNA remain elusive. Results Employing in silico analysis, we identify 281 mitochondrial tRNA homologs in the human genome, which we term nimtRNAs (nuclear intronic mitochondrial-derived tRNAs), being contained within introns of 76 nuclear host genes. Despite base changes in nimtRNAs when compared to their mtRNA homologs, a canonical tRNA cloverleaf structure is maintained. To address potential functions of intronic nimtRNAs, we insert them into introns of constitutive and alternative splicing reporters and demonstrate that nimtRNAs promote pre-mRNA splicing, dependent on the number and positioning of nimtRNA genes and splice site recognition efficiency. A mutational analysis reveals that the nimtRNA cloverleaf structure is required for the observed splicing increase. Utilizing a CRISPR/Cas9 approach, we show that a partial deletion of a single endogenous nimtRNALys within intron 28 of the PPFIBP1 gene decreases inclusion of the downstream-located exon 29 of the PPFIBP1 mRNA. By employing a pull-down approach followed by mass spectrometry, a 3′-splice site-associated protein network is identified, including KHDRBS1, which we show directly interacts with nimtRNATyr by an electrophoretic mobility shift assay. Conclusions We propose that nimtRNAs, along with associated protein factors, can act as a novel class of intronic splicing regulatory elements in the human genome by participating in the regulation of splicing.

Functional variants in hematopoietic transcription factor footprints and their roles in the risk of immune system diseases

2021 ◽  
Author(s):  
Naoto Kubota ◽  
Mikita Suyama
Keyword(s):  
Transcription Factor ◽  
Immune System ◽  
Human Genome ◽  
Disease Risk ◽  
Regulatory Elements ◽  
Molecular Pathogenesis ◽  
Protein Coding ◽  
Immune System Diseases ◽  
Regulatory Variants ◽  
Functional Variants

AbstractGenome-wide association studies (GWAS) have been performed to identify thousands of variants in the human genome as disease risk markers, but functional variants that actually affect gene regulation and their genomic features remain largely unknown. Here we performed a comprehensive survey of functional variants in the regulatory elements of the human genome. We integrated hematopoietic transcription factor (TF) footprints datasets generated by ENCODE project with multiple quantitative trait locus (QTL) datasets (eQTL, caQTL, bQTL, and hQTL) and investigated the associations of functional variants and immune system disease risk. We identified candidate regulatory variants highly linked with GWAS lead variants and found that they were strongly enriched in active enhancers in hematopoietic cells, emphasizing the clinical relevance of enhancers in disease risk. Moreover, we found some strong relationships between traits and hematopoietic cell types or TFs. We highlighted some credible regulatory variants and found that a variant, rs2291668, which potentially functions in the molecular pathogenesis of multiple sclerosis, is located within a TF footprint present in a protein-coding exon of the TNFSF14 gene, indicating that protein-coding exons as well as noncoding regions can possess clinically relevant regulatory elements. Collectively, our results shed light on the molecular pathogenesis of immune system diseases. The methods described in this study can readily be applied to the study of the risk factors of other diseases.

scholarly journals Integrative analysis of public ChIP-seq experiments reveals a complex multi-cell regulatory landscape

2014 ◽  
Vol 43 (4) ◽  
pp. e27-e27 ◽  
Author(s):  
Aurélien Griffon ◽  
Quentin Barbier ◽  
Jordi Dalino ◽  
Jacques van Helden ◽  
Salvatore Spicuglia ◽  
...  
Keyword(s):  
Human Genome ◽  
Enrichment Analysis ◽  
Search Space ◽  
Regulatory Elements ◽  
Data Sets ◽  
Analysis Tool ◽  
Coding Regions ◽  
Genome Wide ◽  
Public Data ◽  
Cancer Genomes

Abstract The large collections of ChIP-seq data rapidly accumulating in public data warehouses provide genome-wide binding site maps for hundreds of transcription factors (TFs). However, the extent of the regulatory occupancy space in the human genome has not yet been fully apprehended by integrating public ChIP-seq data sets and combining it with ENCODE TFs map. To enable genome-wide identification of regulatory elements we have collected, analysed and retained 395 available ChIP-seq data sets merged with ENCODE peaks covering a total of 237 TFs. This enhanced repertoire complements and refines current genome-wide occupancy maps by increasing the human genome regulatory search space by 14% compared to ENCODE alone, and also increases the complexity of the regulatory dictionary. As a direct application we used this unified binding repertoire to annotate variant enhancer loci (VELs) from H3K4me1 mark in two cancer cell lines (MCF-7, CRC) and observed enrichments of specific TFs involved in biological key functions to cancer development and proliferation. Those enrichments of TFs within VELs provide a direct annotation of non-coding regions detected in cancer genomes. Finally, full access to this catalogue is available online together with the TFs enrichment analysis tool (http://tagc.univ-mrs.fr/remap/).

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