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.

Genetic variation within transcriptional regulatory elements and its implications for human disease

2014 ◽  
Vol 395 (12) ◽  
pp. 1453-1460 ◽  
Author(s):  
Alvaro Rada-Iglesias
Keyword(s):  
Genetic Variation ◽  
Genetic Variants ◽  
Large Scale ◽  
Complex Disease ◽  
Regulatory Elements ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory ◽  
Genomic Studies ◽  
Human Genomic ◽  
Effective Diagnosis

Abstract Common human pathologies have a complicated etiology involving both genetic and environmental risk factors. Moreover, the genetic basis of these disorders is also complex, with multiple and weak genetic variants contributing to disease susceptibility. In addition, most of these risk genetic variants occur outside genes, within the vast non-coding human genomic space. In this review I first illustrate how large-scale genomic studies aimed at mapping cis-regulatory elements in the human genome are facilitating the identification of disease-causative non-coding genetic variation. I then discuss some of the challenges that remain to be solved before the pathological consequences of non-coding genetic variation can be fully appreciated. Ultimately, revealing the genetics of human complex disease can be a critical step towards more personalized and effective diagnosis and treatments.

scholarly journals Intra- and inter-chromosomal chromatin interactions mediate genetic effects on regulatory networks

2017 ◽  
Author(s):  
O. Delaneau ◽  
M. Zazhytska ◽  
C. Borel ◽  
C. Howald ◽  
S. Kumar ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Cell Types ◽  
Regulatory Elements ◽  
Regulatory Domains ◽  
Regulatory Variants ◽  
Chromatin Interactions ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Cell Type Specific ◽  
Cis And Trans

SummaryGenome-wide studies on the genetic basis of gene expression and the structural properties of chromatin have considerably advanced our understanding of the function of the human genome. However, it remains unclear how structure relates to function and, in this work, we aim at bridging both by assembling a dataset that combines the activity of regulatory elements (e.g. enhancers and promoters), expression of genes and genetic variations of 317 individuals and across two cell types. We show that the regulatory activity is structured within 12,583 Cis Regulatory Domains (CRDs) that are cell type specific and highly reflective of the local (i.e. Topologically Associating Domains) and global (i.e. A/B nuclear compartments) nuclear organization of the chromatin. These CRDs essentially delimit the sets of active regulatory elements involved in the transcription of most genes, thereby capturing complex regulatory networks in which the effects of regulatory variants are propagated and combined to finally mediate expression Quantitative Trait Loci. Overall, our analysis reveals the complexity and specificity of cis and trans regulatory networks and their perturbation by genetic variation.

scholarly journals Identification of transcriptional regulatory elements in human mitochondrial DNA by linker substitution analysis.

1989 ◽  
Vol 9 (3) ◽  
pp. 1200-1211 ◽  
Author(s):  
J N Topper ◽  
D A Clayton
Keyword(s):  
Mitochondrial Dna ◽  
Transcription Initiation ◽  
Regulatory Elements ◽  
Base Pairs ◽  
Transcriptional Initiation ◽  
Human Mitochondrial Dna ◽  
Transcriptional Regulatory Elements ◽  
Regulatory Domains ◽  
Transcriptional Regulatory ◽  
Minimal Sequences

Human mitochondrial DNA contains two major promoters, one for transcription of each strand of the helix. Previous mapping and mutagenesis data have localized these regulatory elements and have suggested regions important to their function. In order to define, at high resolution, the sequences critical for accurate and efficient transcriptional initiation, a linker substitution analysis of the entire promoter region was performed. Each promoter was shown to consist of approximately 50 base pairs comprising two functionally distinct elements. These and previous data strongly support a mode of transcription initiation requiring minimal sequences surrounding the initiation sites that are likely interactive with core polymerase and upstream regulatory domains capable of binding a transcription factor that modulates the efficiency of transcription initiation. Furthermore, in at least one case, this upstream regulatory domain is capable of operating bidirectionally.

Identification of transcriptional regulatory elements in human mitochondrial DNA by linker substitution analysis

1989 ◽  
Vol 9 (3) ◽  
pp. 1200-1211
Author(s):  
J N Topper ◽  
D A Clayton
Keyword(s):  
Mitochondrial Dna ◽  
Transcription Initiation ◽  
Regulatory Elements ◽  
Base Pairs ◽  
Transcriptional Initiation ◽  
Human Mitochondrial Dna ◽  
Transcriptional Regulatory Elements ◽  
Regulatory Domains ◽  
Transcriptional Regulatory ◽  
Minimal Sequences

Human mitochondrial DNA contains two major promoters, one for transcription of each strand of the helix. Previous mapping and mutagenesis data have localized these regulatory elements and have suggested regions important to their function. In order to define, at high resolution, the sequences critical for accurate and efficient transcriptional initiation, a linker substitution analysis of the entire promoter region was performed. Each promoter was shown to consist of approximately 50 base pairs comprising two functionally distinct elements. These and previous data strongly support a mode of transcription initiation requiring minimal sequences surrounding the initiation sites that are likely interactive with core polymerase and upstream regulatory domains capable of binding a transcription factor that modulates the efficiency of transcription initiation. Furthermore, in at least one case, this upstream regulatory domain is capable of operating bidirectionally.

Identification of transcriptional elements within the long terminal repeat of Rous sarcoma virus

1983 ◽  
Vol 3 (10) ◽  
pp. 1834-1845
Author(s):  
G M Gilmartin ◽  
J T Parsons
Keyword(s):  
Long Terminal Repeat ◽  
Virus Replication ◽  
Rous Sarcoma Virus ◽  
Regulatory Elements ◽  
Terminal Repeat ◽  
Tata Box ◽  
Transcriptional Regulatory Elements ◽  
Rous Sarcoma ◽  
Transcriptional Regulatory ◽  
Sarcoma Virus

Transcriptional regulatory elements within the Rous sarcoma virus long terminal repeat were examined by the construction of a series of deletions and small insertions within the U3 region of the long terminal repeat. The analysis of these mutations in chicken embryo cells and COS cells permitted the identification of important transcriptional regulatory elements. Sequences within the region 31 to 18 base pairs upstream of the RNA cap site (-31 to -18), encompassing a TATA box-like sequence, function in the selection of the correct site of transcription initiation and, in addition, augment the efficiency of transcription. These sequences are essential for virus replication. Sequences within the region -79 to -59, overlapping a CAAT box-like sequence, are not required for virus replication and have no obvious effect on viral RNA transcription in the presence of an intact TATA box. However, in mutants lacking a functional TATA sequence, mutations in this region serve to decrease the efficiency of correct transcriptional initiation events.

scholarly journals Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens

2021 ◽  
Vol 7 (27) ◽  
pp. eabf5733
Author(s):  
Rui Lopes ◽  
Kathleen Sprouffske ◽  
Caibin Sheng ◽  
Esther C. H. Uijttewaal ◽  
Adriana Emma Wesdorp ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regulatory Networks ◽  
Essential Role ◽  
Regulatory Elements ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory ◽  
Functional Relevance ◽  
Genome Scale ◽  
Transcription Program

Millions of putative transcriptional regulatory elements (TREs) have been cataloged in the human genome, yet their functional relevance in specific pathophysiological settings remains to be determined. This is critical to understand how oncogenic transcription factors (TFs) engage specific TREs to impose transcriptional programs underlying malignant phenotypes. Here, we combine cutting edge CRISPR screens and epigenomic profiling to functionally survey ≈15,000 TREs engaged by estrogen receptor (ER). We show that ER exerts its oncogenic role in breast cancer by engaging TREs enriched in GATA3, TFAP2C, and H3K27Ac signal. These TREs control critical downstream TFs, among which TFAP2C plays an essential role in ER-driven cell proliferation. Together, our work reveals novel insights into a critical oncogenic transcription program and provides a framework to map regulatory networks, enabling to dissect the function of the noncoding genome of cancer cells.

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