scholarly journals Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression

2017 ◽  
Author(s):  
Camille Berthelot ◽  
Diego Villar ◽  
Julie E. Horvath ◽  
Duncan T. Odom ◽  
Paul Flicek
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
List Type ◽  
Enhancer Activity ◽  
Expression Levels ◽  
Mammalian Gene ◽  
Highly Expressed Genes ◽  
Regulatory Landscape ◽  
Regulatory Landscapes ◽  
Mammalian Gene Expression

AbstractTo gain insight into how mammalian gene expression is controlled by rapidly evolving regulatory elements, we jointly analysed promoter and enhancer activity with downstream transcription levels in liver samples from twenty species. Genes associated with complex regulatory landscapes generally exhibit high expression levels that remain evolutionarily stable. While the number of regulatory elements is the key driver of transcriptional output and resilience, regulatory conservation matters: elements active across mammals most effectively stabilise gene expression. In contrast, recently-evolved enhancers typically contribute weakly, consistent with their high evolutionary plasticity. These effects are observed across the entire mammalian clade and robust to potential confounders, such as gene expression level. Overall, our results illuminate how the evolutionary stability of gene expression is profoundly entwined with both the number and conservation of surrounding promoters and enhancers.HighlightsGene expression levels and stability are linked to the number of elements in the regulatory landscape.Conserved regulatory elements associate with tightly controlled, highly expressed genes.Recently evolved enhancers weakly influence gene expression, but promoters are similarly active regardless of conservation.The interplay between complexity of the regulatory landscape and conservation of individual promoters and enhancers shapes gene expression in mammals.

scholarly journals Imprinted gene expression at the Dlk1-Dio3 cluster is controlled by both maternal and paternal IG-DMRs in a tissue-specific fashion

2019 ◽  
Author(s):  
Katherine A. Alexander ◽  
María J. García-García
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Enhancer Activity ◽  
Enhancer Element ◽  
Tissue Specific ◽  
Imprinted Gene ◽  
Imprinting Control Region ◽  
Regulatory Landscape ◽  
Insight Into ◽  
Different Tissues

ABSTRACTImprinting at the Dlk1-Dio3 cluster is controlled by the IG-DMR, an imprinting control region differentially methylated between maternal and paternal chromosomes. The maternal IG-DMR is essential for imprinting control, functioning as a cis enhancer element. Meanwhile, DNA methylation at the paternal IG-DMR is thought to prevent enhancer activity. To explore whether suppression of enhancer activity at the methylated IG-DMR requires the transcriptional repressor TRIM28, we analyzed Trim28chatwo embryos and performed epistatic experiments with IG-DMR deletion mutants. We found that while TRIM28 regulates the enhancer properties of the paternal IG-DMR, it also controls imprinting through other mechanisms. Additionally, we found that the paternal IG-DMR, previously deemed dispensable for imprinting, is required in certain tissues, demonstrating that imprinting is regulated in a tissue-specific manner. Using PRO-seq to analyze nascent transcription, we identified 30 novel transcribed regulatory elements, including 23 that are tissue-specific. These results demonstrate that different tissues have a distinctive regulatory landscape at the Dlk1-Dio3 cluster and provide insight into potential mechanisms of tissue-specific imprinting control. Together, our findings challenge the premise that Dlk1-Dio3 imprinting is regulated through a single mechanism and demonstrate that different tissues use distinct strategies to accomplish imprinted gene expression.

scholarly journals Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression

2017 ◽  
Vol 2 (1) ◽  
pp. 152-163 ◽  
Author(s):  
Camille Berthelot ◽  
Diego Villar ◽  
Julie E. Horvath ◽  
Duncan T. Odom ◽  
Paul Flicek
Keyword(s):  
Gene Expression ◽  
Mammalian Gene ◽  
Regulatory Landscapes ◽  
Mammalian Gene Expression

scholarly journals The marked diversity of unique cortical enhancers enables neuron-specific tools by Enhancer-Driven Gene Expression

2018 ◽  
Author(s):  
Stefan Blankvoort ◽  
Menno P. Witter ◽  
James Noonan ◽  
Justin Cotney ◽  
Cliff Kentros
Keyword(s):  
Gene Expression ◽  
Neural Circuit ◽  
Neuronal Cell ◽  
Cell Types ◽  
Regulatory Elements ◽  
List Type ◽  
Enhancer Activity ◽  
Genetic Tools ◽  
Transgenic Lines ◽  
Genetic Mechanisms

SUMMARYUnderstanding neural circuit function requires individually addressing their component parts: specific neuronal cell types. However, not only do the precise genetic mechanisms specifying neuronal cell types remain obscure, access to these neuronal cell types by transgenic techniques also remains elusive. While most genes are expressed in the brain, the vast majority are expressed in many different kinds of neurons, suggesting that promoters alone are not sufficiently specific to distinguish cell types. However, there are orders of magnitude more distal genetic cis-regulatory elements controlling transcription (i.e. enhancers), so we screened for enhancer activity in microdissected samples of mouse cortical subregions. This identified thousands of novel putative enhancers, many unique to particular cortical subregions. Pronuclear injection of expression constructs containing such region-specific enhancers resulted in transgenic lines driving expression in distinct sets of cells specifically in the targeted cortical subregions, even though the parent gene’s promoter was relatively nonspecific. These data showcase the promise of utilizing the genetic mechanisms underlying the specification of diverse neuronal cell types for the development of genetic tools potentially capable of targeting any neuronal circuit of interest, an approach we call Enhancer-Driven Gene Expression (EDGE).HighlightsEnhancer ChIP-seq of cortical subregions reveals 59372 putative enhancers.3740 of these are specific to particular cortical subregions.This reflects the remarkable anatomical diversity of the adult cortex.Unique enhancers provide a means to make targeted cell-type specific genetic tools.

Gene-regulatory elements may change the amount, timing, or location of gene expression, cis-Regulation therapy platforms might become a gene therapy to treat many genetic diseases

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Expression ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Tissue Type ◽  
Gene Promoters ◽  
Expression Levels ◽  
Cis Regulation ◽  
Gene Regulatory Elements ◽  
Gene Regulatory ◽  
Gene Expression Levels

Changes in gene expression levels above or below a particular threshold may have a dramatic impact on phenotypes, leading to a wide spectrum of human illnesses. Gene-regulatory elements, also known as cis-regulatory elements (CREs), may change the amount, timing, or location (cell/tissue type) of gene expression, whereas mutations in a gene's coding sequence may result in lower or higher gene expression levels resulting in protein loss or gain. Loss-of-function mutations in both genes produce recessive human illness, while haploinsufficient mutations in 65 genes are also known to be deleterious due to function gain, according to the ClinVar1 and ClinGen3 databases. CREs are promoters living near to a gene's transcription start site and switching it on at predefined times, places, and levels. Other distal CREs, like enhancers and silencers, are temporal and tissue-specific control promoters. Enhancers activate promoters, commonly referred to as "promoters," whereas silencers turn them off. Insulators also restrict promiscuous interactions between enhancers and gene promoters. Systematic genomic approaches can help understand the cis-regulatory circuitry of gene expression by highly detecting and functionally defining these CREs. This includes the new use of CRISPR–CRISPR-associated protein 9 (CRISPR–Cas9) and other editing approaches to discover CREs. Cis-Regulation therapy (CRT) provides many promises to heal human ailments. CRT may be used to upregulate or downregulate disease-causing genes due to lower or higher levels of expression, and it may also be used to precisely adjust the expression of genes that assist in alleviating disease features. CRT may employ proteins that generate epigenetic modifications like methylation, histone modification, or gene expression regulation looping. Weighing CRT's advantages and downsides against alternative treatment methods is crucial. CRT platforms might become a practical technique to treat many genetic diseases that now lack treatment alternatives if academics, patient communities, clinicians, regulators and industry work together.

scholarly journals Global quantification of mammalian gene expression control

Nature ◽  
2011 ◽  
Vol 473 (7347) ◽  
pp. 337-342 ◽  
Author(s):  
Björn Schwanhäusser ◽  
Dorothea Busse ◽  
Na Li ◽  
Gunnar Dittmar ◽  
Johannes Schuchhardt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mammalian Gene ◽  
Expression Control ◽  
Gene Expression Control ◽  
Mammalian Gene Expression

scholarly journals Assessing the Conservation of Mammalian Gene Expression Using High-Density Exon Arrays

2007 ◽  
Vol 24 (7) ◽  
pp. 1577-1577
Author(s):  
Y. Xing ◽  
Z. Ouyang ◽  
K. Kapur ◽  
M. P. Scott ◽  
W. H. Wong
Keyword(s):  
Gene Expression ◽  
High Density ◽  
Exon Arrays ◽  
Mammalian Gene ◽  
Mammalian Gene Expression

The kinetics of mammalian gene expression

BioEssays ◽  
1991 ◽  
Vol 13 (12) ◽  
pp. 667-674 ◽  
Author(s):  
James L. Hargrove ◽  
Martin G. Hulsey ◽  
Elmus G. Beale
Keyword(s):  
Gene Expression ◽  
Mammalian Gene ◽  
Kinetics Of ◽  
Mammalian Gene Expression

A “GC-rich” method for mammalian gene expression: A dominant role of non-coding DNA GC content in regulation of mammalian gene expression

2010 ◽  
Vol 53 (1) ◽  
pp. 94-100 ◽  
Author(s):  
Qian Jia ◽  
HongTao Wu ◽  
XingJun Zhou ◽  
Jian Gao ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dominant Role ◽  
Gc Content ◽  
Mammalian Gene ◽  
Mammalian Gene Expression
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