scholarly journals Dysregulated Transcriptional Control in Prostate Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2883 ◽  
Author(s):  
Simon J. Baumgart ◽  
Ekaterina Nevedomskaya ◽  
Bernard Haendler
Keyword(s):  
Prostate Cancer ◽  
Drug Targets ◽  
Transcriptional Control ◽  
Regulatory Elements ◽  
Protein Coding ◽  
Coding Regions ◽  
Super Enhancer ◽  
Position Coding ◽  
Transcription Dysregulation ◽  
Dna Regulatory Elements

Recent advances in whole-genome and transcriptome sequencing of prostate cancer at different stages indicate that a large number of mutations found in tumors are present in non-protein coding regions of the genome and lead to dysregulated gene expression. Single nucleotide variations and small mutations affecting the recruitment of transcription factor complexes to DNA regulatory elements are observed in an increasing number of cases. Genomic rearrangements may position coding regions under the novel control of regulatory elements, as exemplified by the TMPRSS2-ERG fusion and the amplified enhancer identified upstream of the androgen receptor (AR) gene. Super-enhancers are increasingly found to play important roles in aberrant oncogenic transcription. Several players involved in these processes are currently being evaluated as drug targets and may represent new vulnerabilities that can be exploited for prostate cancer treatment. They include factors involved in enhancer and super-enhancer function such as bromodomain proteins and cyclin-dependent kinases. In addition, non-coding RNAs with an important gene regulatory role are being explored. The rapid progress made in understanding the influence of the non-coding part of the genome and of transcription dysregulation in prostate cancer could pave the way for the identification of novel treatment paradigms for the benefit of patients.

scholarly journals The open targets post-GWAS analysis pipeline

2020 ◽  
Vol 36 (9) ◽  
pp. 2936-2937 ◽  
Author(s):  
Gareth Peat ◽  
William Jones ◽  
Michael Nuhn ◽  
José Carlos Marugán ◽  
William Newell ◽  
...  
Keyword(s):  
Drug Targets ◽  
Gene Expression Regulation ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Protein Coding ◽  
Data Resource ◽  
Coding Regions ◽  
Genome Wide ◽  
Causal Genes ◽  
Interactive Data

Abstract Motivation Genome-wide association studies (GWAS) are a powerful method to detect even weak associations between variants and phenotypes; however, many of the identified associated variants are in non-coding regions, and presumably influence gene expression regulation. Identifying potential drug targets, i.e. causal protein-coding genes, therefore, requires crossing the genetics results with functional data. Results We present a novel data integration pipeline that analyses GWAS results in the light of experimental epigenetic and cis-regulatory datasets, such as ChIP-Seq, Promoter-Capture Hi-C or eQTL, and presents them in a single report, which can be used for inferring likely causal genes. This pipeline was then fed into an interactive data resource. Availability and implementation The analysis code is available at www.github.com/Ensembl/postgap and the interactive data browser at postgwas.opentargets.io.

scholarly journals Human to yeast pathway transplantation: cross-species dissection of the adenine de novo pathway regulatory node

2017 ◽  
Author(s):  
Neta Agmon ◽  
Jasmine Temple ◽  
Zuojian Tang ◽  
Tobias Schraink ◽  
Maayan Baron ◽  
...  
Keyword(s):  
Yeast Strain ◽  
Transcriptional Control ◽  
De Novo ◽  
Enzyme Level ◽  
Yeast Cells ◽  
Protein Coding ◽  
Coding Regions ◽  
Human Proteins ◽  
Human Ortholog ◽  
Yeast Genes

AbstractPathway transplantation from one organism to another represents a means to a more complete understanding of a biochemical or regulatory process. The purine biosynthesis pathway, a core metabolic function, was transplanted from human to yeast. We replaced the entireSaccharomyces cerevisiaeadenine de novo pathway with the cognate human pathway components. A yeast strain was “humanized” for the full pathway by deleting all relevant yeast genes completely and then providing the human pathway in trans using a neochromosome expressing the human protein coding regions under the transcriptional control of their cognate yeast promoters and terminators. The “humanized” yeast strain grows in the absence of adenine, indicating complementation of the yeast pathway by the full set of human proteins. While the strain with the neochromosome is indeed prototrophic, it grows slowly in the absence of adenine. Dissection of the phenotype revealed that the human ortholog ofADE4, PPAT, shows only partial complementation. We have used several strategies to understand this phenotype, that point toPPAT/ADE4as the central regulatory node. Pathway metabolites are responsible for regulatingPPAT’sprotein abundance through transcription and proteolysis as well as its enzymatic activity by allosteric regulation in these yeast cells. Extensive phylogenetic analysis of PPATs from diverse organisms hints at adaptations of the enzyme-level regulation to the metabolite levels in the organism. Finally, we isolated specific mutations in PPAT as well as in other genes involved in the purine metabolic network that alleviate incomplete complementation byPPATand provide further insight into the complex regulation of this critical metabolic pathway.

scholarly journals Mutations in gene regulatory elements linked to human limb malformations

2019 ◽  
Vol 57 (6) ◽  
pp. 361-370
Author(s):  
Karol Nowosad ◽  
Ewa Hordyjewska-Kowalczyk ◽  
Przemko Tylzanowski
Keyword(s):  
Regulatory Elements ◽  
Regulatory Function ◽  
Protein Coding ◽  
Coding Regions ◽  
Technological Advances ◽  
Non Coding Rna ◽  
Limb Malformations ◽  
Gene Regulatory Elements ◽  
Chromatin Organisation ◽  
Human Limb

Most of the human genome has a regulatory function in gene expression. The technological progress made in recent years permitted the revision of old and discovery of new mutations outside of the protein-coding regions that do affect human limb morphology. Steadily increasing discovery rate of such mutations suggests that until now the largely neglected part of the genome rises to its well-deserved prominence. In this review, we describe the recent technological advances permitting this unprecedented advance in identifying non-coding mutations. We especially focus on the mutations in cis-regulatory elements such as enhancers, and trans-regulatory elements such as miRNA and long non-coding RNA, linked to hereditary or inborn limb defects. We also discuss the role of chromatin organisation and enhancer–promoter interactions in the aetiology of limb malformations.

scholarly journals How to find genomic regions relevant for gene regulation

2021 ◽  
Vol 33 (2) ◽  
pp. 157-165
Author(s):  
Xuanzong Guo ◽  
Uwe Ohler ◽  
Ferah Yildirim
Keyword(s):  
Functional Characterization ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
High Throughput Analysis ◽  
Protein Coding ◽  
Coding Regions ◽  
The Past ◽  
Genomic Regions ◽  
Regulatory Functions

Abstract Genetic variants associated with human diseases are often located outside the protein coding regions of the genome. Identification and functional characterization of the regulatory elements in the non-coding genome is therefore of crucial importance for understanding the consequences of genetic variation and the mechanisms of disease. The past decade has seen rapid progress in high-throughput analysis and mapping of chromatin accessibility, looping, structure, and occupancy by transcription factors, as well as epigenetic modifications, all of which contribute to the proper execution of regulatory functions in the non-coding genome. Here, we review the current technologies for the definition and functional validation of non-coding regulatory regions in the genome.

scholarly journals Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

Gut ◽  
2019 ◽  
Vol 68 (5) ◽  
pp. 928-941 ◽  
Author(s):  
Claartje Aleid Meddens ◽  
Amy Catharina Johanna van der List ◽  
Edward Eelco Salomon Nieuwenhuis ◽  
Michal Mokry
Keyword(s):  
Therapeutic Potential ◽  
Association Studies ◽  
Cell Types ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Protein Coding ◽  
Dna Regulatory Elements ◽  
Coding Variants ◽  
Novel Therapeutic

Genome-wide association studies have identified over 200 loci associated with IBD. We and others have recently shown that, in addition to variants in protein-coding genes, the majority of the associated loci are related to DNA regulatory elements (DREs). These findings add a dimension to the already complex genetic background of IBD. In this review we summarise the existing evidence on the role of DREs in IBD. We discuss how epigenetic research can be used in candidate gene approaches that take non-coding variants into account and can help to pinpoint the essential pathways and cell types in the pathogenesis of IBD. Despite the increased level of genetic complexity, these findings can contribute to novel therapeutic options that target transcription factor binding and enhancer activity. Finally, we summarise the future directions and challenges of this emerging field.

scholarly journals Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

Nature ◽  
2021 ◽  
Author(s):  
Lanbo Xiao ◽  
Abhijit Parolia ◽  
Yuanyuan Qiao ◽  
Pushpinder Bawa ◽  
Sanjana Eyunni ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cell ◽  
Regulatory Elements ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Super Enhancer ◽  
Potent Inhibition ◽  
Promising Therapeutic Approach ◽  
Atpase Subunits ◽  
Xenograft Models

AbstractThe switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

scholarly journals G-quadruplex-forming sequences as potential drivers of genetic diversity in primate protein coding genes

2020 ◽  
Author(s):  
Manuel Jara-Espejo ◽  
Sergio Roberto Peres Line
Keyword(s):  
Genetic Diversity ◽  
Amino Acid ◽  
Protein Function ◽  
Evolutionary Dynamics ◽  
Regulatory Elements ◽  
Evolutionary Trend ◽  
Protein Coding ◽  
Coding Regions ◽  
Mutational Pattern ◽  
Species Specific

ABSTRACTWhile non-coding G-quadruplexes (G4s) act as conserved regulatory elements when located in gene promoter and splice sites, the G4 evolutionary conservation in protein coding regions have been low explored. To address the evolutionary dynamics acting on coding G4, we mapped and characterized potential G4-forming sequences across twenty-four primate’s gene orthologous. We found that potentially more stable G4 motifs exist in coding regions following a species-specific trend. Moreover, these motifs depicted the least conserved sites across primates at both the DNA and amino acid levels and are characterized by an indel-rich mutational pattern. This trend was not observed for less stable G4 motifs. A deeper analysis revealed that [G>=3N1]4 motifs, depicting potentially most stable G4s, were associated with the lowest conservation and highest indel frequencies. This mutational pattern was more evident when G4-associated amino acid regions were analyzed. We discuss the possibility of an overall conservation of less/moderate stability G4, while more stable G4 may be preserved or arises in a species-specific manner, which may explain their low conservation. Since structure-prone motifs, including G4, have the potential to induce genomic instability, this evolutionary trend may contribute to avoid broad deleterious effects driven by stable G4 on protein function while promoting genetic diversity across close-related species.

scholarly journals Recommendations for clinical interpretation of variants found in non-coding regions of the genome

2021 ◽  
Author(s):  
Jamie M Ellingford ◽  
Joo Wook Ahn ◽  
Richard D Bagnall ◽  
Diana Baralle ◽  
Stephanie Barton ◽  
...  
Keyword(s):  
Genetic Disorders ◽  
Regulatory Elements ◽  
Monogenic Disease ◽  
Coding Region ◽  
Clinical Genetic ◽  
Protein Coding ◽  
Clinical Genetic Testing ◽  
Coding Regions ◽  
Current Guidelines

Purpose: The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. Methods: We convened a panel of clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. Results: We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for these variants. Conclusion: These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.

scholarly journals Building a sequence map of the pig pan-genome from multiple de novo assemblies and Hi-C data

2018 ◽  
Author(s):  
Xiaomeng Tian ◽  
Ran Li ◽  
Weiwei Fu ◽  
Yan Li ◽  
Xihong Wang ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
De Novo ◽  
3D Structure ◽  
Regulatory Elements ◽  
Protein Coding ◽  
Web Based ◽  
Coding Regions ◽  
Pan Genome ◽  
Enhanced Resolution ◽  
Genome Assemblies

AbstractPigs (Sus scrofa) exhibit diverse phenotypes in different breeds shaped by the combined effects of various local adaptation and artificial selection. To comprehensively characterize the genetic diversity of pigs, we construct a pig pan-genome by comparing genome assemblies of 11 representative pig breeds with the reference genome (Sscrofa11.1). Approximately 72.5 Mb non-redundant sequences were identified as pan-sequences which were absent from the Sscrofa11.1. On average, 41.7 kb of spurious heterozygous SNPs per individual are removed and 12.9 kb novel SNPs per individual are recovered using pan-genome as the reference for SNP calling, thereby providing enhanced resolution for genetic diversity in pigs. Homolog annotation and analysis using RNA-seq and Hi-C data indicate that these pan-sequences contain protein-coding regions and regulatory elements. These pan-sequences can further improve the interpretation of local 3D structure. The pan-genome as well as the accompanied web-based database will serve as a primary resource for exploration of genetic diversity and promote pig breeding and biomedical research.

scholarly journals Transgenic mouse models in the study of reproduction: insights into GATA protein function

Reproduction ◽  
2014 ◽  
Vol 148 (1) ◽  
pp. R1-R14 ◽  
Author(s):  
Sergei G Tevosian
Keyword(s):  
Protein Function ◽  
Transcriptional Control ◽  
Cell Types ◽  
Regulatory Elements ◽  
Genetically Engineered ◽  
Detailed Knowledge ◽  
P Gene ◽  
Genes Encoding ◽  
Key Factor ◽  
Dna Regulatory Elements

For the past 2 decades, transgenic technology in mice has allowed for an unprecedented insight into the transcriptional control of reproductive development and function. The key factor among the mouse genetic tools that made this rapid advance possible is a conditional transgenic approach, a particularly versatile method of creating gene deletions and substitutions in the mouse genome. A centerpiece of this strategy is an enzyme, Cre recombinase, which is expressed from defined DNA regulatory elements that are active in the tissue of choice. The regulatory DNA element (either genetically engineered or natural) assures Cre expression only in predetermined cell types, leading to the guided deletion of genetically modified (flanked by loxP or ‘floxed’ byloxP) gene loci. This review summarizes and compares the studies in which genes encoding GATA family transcription factors were targeted either globally or by Cre recombinases active in the somatic cells of ovaries and testes. The conditional gene loss experiments require detailed knowledge of the spatial and temporal expression of Cre activity, and the challenges in interpreting the outcomes are highlighted. These studies also expose the complexity of GATA-dependent regulation of gonadal gene expression and suggest that gene function is highly context dependent.

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