Posts Tagged ‘enhancer’

Sequence of events in prostate cancer

October 5, 2018

Sequence of events in prostate #cancer, by @MarkARubin1
http://www.Nature.com/articles/d41586-018-06029-5 Discusses the high prevalence of AR-enhancer amplifications in recent studies
QT:{{”
“Quigley and colleagues performed whole-genome sequencing of 101 samples of metastatic, castration-resistant prostate-cancer tissue obtained from previous studies11,12. The most frequently altered genomic site identified was the AR-enhancer region, which was amplified in 81% of samples. The high prevalence of this type of amplification is notable because enhancer amplifications identified so far for other cancer types generally arise at much lower
frequency13–16. Moreover, the high prevalence of this AR-enhancer amplification in the data presented by Viswanathan and Quigley contrasts with its occurrence in only 1 of 54 previously published whole-genome sequences of prostate-cancer samples obtained before clinical treatment had commenced17.”
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promoter/enhancer categorization and Encyclopedia

July 1, 2017

Genome-wide characterization of..promoters w…enhancer functions http://www.Nature.com/ng/journal/v49/n7/full/ng.3884.html Blurs distinction betw these, suggests flexibility

Genome-wide characterization of mammalian promoters with distal enhancer functions

Lan T M Dao,
Ariel O Galindo-Albarrán,
Jaime A Castro-Mondragon,
Charlotte Andrieu-Soler,
Alejandra Medina-Rivera,
Charbel Souaid,
Guillaume Charbonnier,
Aurélien Griffon,
Laurent Vanhille,
Tharshana Stephen,
Jaafar Alomairi,
David Martin,
Magali Torres,
Nicolas Fernandez,
Eric Soler,
Jacques van Helden,
Denis Puthier
& Salvatore Spicuglia

Promoting transcription over long distances

Rui R Catarino,
Christoph Neumayr
& Alexander Stark

Nature Genetics 49, 972–973 (2017) doi:10.1038/ng.3904
28 June 2017

http://www.nature.com/ng/journal/v49/n7/full/ng.3884.html

http://www.nature.com/ng/journal/v49/n7/full/ng.3904.html

QT:{{”
“Should we be surprised that promoters can function as enhancers—or better—that enhancers and promoter regions can overlap? Probably not: the habit of annotating different genomic regions with distinct labels ignores the fact that DNA sequences typically encode different genetic functions in a rather flexible manner. Enhancers and promoters are determined by the presence of short degenerate motifs, and even protein-coding regions display flexibility due to the degeneracy of the genetic code. Therefore, a single DNA sequence can encode different types of functions, including enhancer function of protein-coding regions or—as shown now—enhancer function of
promoters.”
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Enhancer Evolution across 20 Mammalian Species: Cell

November 28, 2015

#Enhancer Evolution across 20 Mammal[s is faster than for promoters] by @PaulFlicek lab http://www.cell.com/cell/abstract/S0092-8674(15)00007-0 H3K27ac & H3K4me3 #chipseq

http://www.cell.com/cell/abstract/S0092-8674(15)00007-0

Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters : Nature Biotechnology : Nature Publishing Group

June 10, 2015

Segal cites: Measurements of 1000s of…designed promoters
http://www.nature.com/nbt/journal/v30/n6/full/nbt.2205.html Num. binding sites correlated w/ expr., for 1st few #ICSG2015

Unraveling determinants of transcription factor binding outside the core binding site

June 8, 2015

Segal cites: Determinants of TF binding outside the core binding site http://genome.cshlp.org/content/early/2015/06/05/gr.185033.114.abstract Large-scale measurement of affinity #ICSG2015

Extensive evolutionary changes in regulatory element activity during human origins are associated with altered gene expression and positive selection. PLoS Genet. 2012

April 12, 2015

Changes in [DHS] #regulatory element activity…[over 3 primates] associated w/ altered…expression & pos. selection
http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002789

DHS across 3 primates finds species specific sites associated with differential expression & positive selection

Shibata Y, Sheffield NC, Fedrigo O, Babbitt CC, Wortham M, Tewari AK, London D, Song L, Lee BK, Iyer VR, Parker SC, Margulies EH, Wray GA, Furey TS, Crawford GE*. Extensive evolutionary changes in regulatory element activity during human origins are
associated with altered gene expression and positive selection. PLoS Genet. 2012 Jun; 8(6):e1002789. doi: 10.1371/journal.pgen.1002789. Epub 2012 Jun 28. PubMed PMID: 22761590; PubMed Central PMCID: PMC3386175

SUMMARY (from csds):

The study is focused on analyzing genotype-phenotype correlation by looking at the evolution of DHS sites across three primate genomes: human, chimp and macaque. By comparing the data they were able to identify common DHS sites across the three species (sites that show similar DHS levels) and also species-specific sites. All the assays were supported by ChiP experiments. The study identified >2000 regulatory elements that were gained/lost since the divergence of
human and chimp. Looking at DNase and RNAseq data the authors show that the enrichment of regulatory elements next to genes with species-specific expression, suggests that the gain or loss of DHS sites impacts transcript abundance. The human DHS sites were enhanced for chromatin marks predictive of enhancers, while common regions were preferentially associated with promoters and insulators. By looking at species specificity, they found that species-specific DHS gains are cell type specific while both species specific DHS gains and losses are subject to positive selection. The common DHS sites are conserved and are suggested to have roles involving transcription and general housekeeping.

Circadian Enhancers Coordinate Multiple Phases of Rhythmic Gene Transcription In Vivo

April 5, 2015

Circadian #Enhancers Coordinate… Rhythmic… Transcription http://www.cell.com/cell/abstract/S0092-8674%2814%2901310-5
Periodicity helps find #eRNAs/enhancers & their targets

Evolution at Two Levels: On Genes and Form

July 23, 2014

Evolution at 2 Levels: Genes &
Formhttp://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0030245 Reg evol likely for genes in mult tissues, w. pleiotropic coding SNPs & mult CRMs

QT:{{”

One critical parameter that affects the relative contribution of different genetic mechanisms to anatomical variation is the pleiotropy of mutations []. In general, it is expected that mutations with greater pleiotropic effects will have more deleterious effects on organismal fitness and will be a less common source of variation in form than mutations with less widespread effects.

Over the past 30 years, several key features of gene structure, function, and regulation in multicellular organisms have emerged that govern the pleiotropy of mutations and thus shape the capacity of species to generate anatomical variation and to evolve (see ). Because of these features, mutations in different genes and different parts of genes (that is, non-coding and coding sequences) can differ
dramatically in their degree of pleiotropy. For example, a mutation in the coding region of a transcription factor that functions in multiple tissues may directly affect all of the genes the protein regulates. In contrast, a mutation in a single cis-regulatory element will affect gene expression only in the domain governed by that element.

The most influential single publication of this era, however, was Susumu Ohno’s book Evolution by Gene Duplication []. Ohno focused on the importance of gene redundancy in allowing “forbidden” mutations to occur that could impart new functions to proteins. His opening motto, “natural selection merely modified, while redundancy created,” reflected a view of natural selection as a largely purifying, conservative process. Ohno insisted that “allelic mutations of already existing gene loci cannot account for major changes in evolution.”

…the estimated rate of gene duplication is about once per gene per 100 million years []. This figure suggests that gene duplication can contribute to genome evolution over longer spans of evolutionary time (for example, greater than 50 million years)….

The human FOXP2 gene encodes a transcription factor, and mutations at the locus were discovered to be associated with a speech and language disorder…. While it would certainly be convenient if the two changes in the FOXP2 protein were functional, the additional hypothesis must be considered that functional regulatory changes might have occurred at theFOXP2 locus. In weighing alternative hypotheses of FOXP2 or any gene’s potential involvement in the evolution of form (or neural circuitry), we should ask the following questions. (i) Is the gene product used in multiple tissues? (ii) Are mutations in the coding sequence known or likely to be pleiotropic? (iii) Does the locus contain multiple cis-regulatory elements?

If the answers are yes to all of these questions, then regulatory sequence evolution is the more likely mode of evolution than coding sequence evolution.

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