scholarly journals Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression

2012 ◽  
Vol 32 (4) ◽  
pp. 897-897
Author(s):  
G. Ling ◽  
A. Sugathan ◽  
T. Mazor ◽  
E. Fraenkel ◽  
D. J. Waxman
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Chromatin Structure ◽  
Regulatory Elements ◽  
Transcriptional Regulatory Elements ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Liver Gene

scholarly journals Predictive modelling of gene expression from transcriptional regulatory elements

2014 ◽  
Vol 16 (4) ◽  
pp. 616-628 ◽  
Author(s):  
David M. Budden ◽  
Daniel G. Hurley ◽  
Edmund J. Crampin
Keyword(s):  
Gene Expression ◽  
Predictive Modelling ◽  
Regulatory Elements ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory

scholarly journals Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery

2018 ◽  
Author(s):  
Xinchen Wang ◽  
David B. Goldstein
Keyword(s):  
Complex Disease ◽  
Genome Wide Association Study ◽  
Regulatory Elements ◽  
Disease Genes ◽  
Transcriptional Regulatory Elements ◽  
Regulatory Domains ◽  
Disease Gene Discovery ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Transcriptional Regulatory

AbstractNon-coding transcriptional regulatory elements are critical for controlling the spatiotemporal expression of genes. Here, we demonstrate that the number of bases in enhancers linked to a gene reflects its disease pathogenicity. Moreover, genes with redundant enhancer domains are depleted of cis-acting genetic variants that disrupt gene expression, and are buffered against the effects of disruptive non-coding mutations. Our results demonstrate that dosage-sensitive genes have evolved robustness to the disruptive effects of genetic variation by expanding their regulatory domains. This resolves a puzzle in the genetic literature about why disease genes are depleted of cis-eQTLs, suggesting that eQTL information may implicate the wrong genes at genome-wide association study loci, and establishes a framework for identifying non-coding regulatory variation with phenotypic consequences.

scholarly journals Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression

2010 ◽  
Vol 30 (23) ◽  
pp. 5531-5544 ◽  
Author(s):  
Guoyu Ling ◽  
Aarathi Sugathan ◽  
Tali Mazor ◽  
Ernest Fraenkel ◽  
David J. Waxman
Keyword(s):  
High Throughput Sequencing ◽  
Strong Association ◽  
Regulatory Elements ◽  
Sequence Motifs ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory ◽  
Mammalian Tissues ◽  
Hypersensitive Sites ◽  
Regulatory Sites

ABSTRACT We have used a simple and efficient method to identify condition-specific transcriptional regulatory sites in vivo to help elucidate the molecular basis of sex-related differences in transcription, which are widespread in mammalian tissues and affect normal physiology, drug response, inflammation, and disease. To systematically uncover transcriptional regulators responsible for these differences, we used DNase hypersensitivity analysis coupled with high-throughput sequencing to produce condition-specific maps of regulatory sites in male and female mouse livers and in livers of male mice feminized by continuous infusion of growth hormone (GH). We identified 71,264 hypersensitive sites, with 1,284 showing robust sex-related differences. Continuous GH infusion suppressed the vast majority of male-specific sites and induced a subset of female-specific sites in male livers. We also identified broad genomic regions (up to ∼100 kb) showing sex-dependent hypersensitivity and similar patterns of GH responses. We found a strong association of sex-specific sites with sex-specific transcription; however, a majority of sex-specific sites were >100 kb from sex-specific genes. By analyzing sequence motifs within regulatory regions, we identified two known regulators of liver sexual dimorphism and several new candidates for further investigation. This approach can readily be applied to mapping condition-specific regulatory sites in mammalian tissues under a wide variety of physiological conditions.

scholarly journals Paupar LncRNA Promotes KAP1 Dependent Chromatin Changes And Regulates Subventricular Zone Neurogenesis

2017 ◽  
Author(s):  
Ioanna Pavlaki ◽  
Farah Alammari ◽  
Bin Sun ◽  
Neil Clark ◽  
Tamara Sirey ◽  
...  
Keyword(s):  
Subventricular Zone ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Neuroblastoma Cell ◽  
Regulatory Protein ◽  
Regulatory Elements ◽  
Loss Of Function ◽  
Transcriptional Regulatory Elements ◽  
Genome Wide

ABSTRACTMany long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet their in vivo roles and molecular mechanisms of action remain poorly understood. Paupar, a CNS expressed lncRNA, controls neuroblastoma cell growth by binding and modulating the activity of genome-wide transcriptional regulatory elements. We show here that Paupar transcript directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation. Paupar promotes KAP1 chromatin occupancy and H3K9me3 deposition at a subset of distal targets, through formation of a DNA binding ribonucleoprotein complex containing Paupar, KAP1 and the PAX6 transcription factor. Paupar-KAP1 genome-wide co-occupancy reveals a 4-fold enrichment of overlap between Paupar and KAP1 bound sequences. Furthermore, both Paupar and Kap1 loss of function in vivo accelerates lineage progression in the mouse postnatal subventricular zone (SVZ) stem cell niche and disrupts olfactory bulb neurogenesis. These observations provide important conceptual insights into the trans-acting modes of lncRNA-mediated epigenetic regulation, the mechanisms of KAP1 genomic recruitment and identify Paupar and Kap1 as regulators of SVZ neurogenesis.

scholarly journals Boundary sequences flanking the mouse tyrosinase locus ensure faithful pattern of gene expression

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Davide Seruggia ◽  
Almudena Fernández ◽  
Marta Cantero ◽  
Ana Fernández-Miñán ◽  
José Luis Gomez-Skarmeta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Expression Patterns ◽  
Regulatory Elements ◽  
Regulatory Sequences ◽  
Cell Type ◽  
Chromosome Conformation ◽  
Control Of Gene Expression ◽  
Cell Type Specific

Abstract Control of gene expression is dictated by cell-type specific regulatory sequences that physically organize the structure of chromatin, including promoters, enhancers and insulators. While promoters and enhancers convey cell-type specific activating signals, insulators prevent the cross-talk of regulatory elements within adjacent loci and safeguard the specificity of action of promoters and enhancers towards their targets in a tissue specific manner. Using the mouse tyrosinase (Tyr) locus as an experimental model, a gene whose mutations are associated with albinism, we described the chromatin structure in cells at two distinct transcriptional states. Guided by chromatin structure, through the use of Chromosome Conformation Capture (3C), we identified sequences at the 5′ and 3′ boundaries of this mammalian gene that function as enhancers and insulators. By CRISPR/Cas9-mediated chromosomal deletion, we dissected the functions of these two regulatory elements in vivo in the mouse, at the endogenous chromosomal context, and proved their mechanistic role as genomic insulators, shielding the Tyr locus from the expression patterns of adjacent genes.

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