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 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 long non-coding RNA Dali is an epigenetic regulator of neural differentiation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Vladislava Chalei ◽  
Stephen N Sansom ◽  
Lesheng Kong ◽  
Sheena Lee ◽  
Juan F Montiel ◽  
...  
Keyword(s):  
Neural Differentiation ◽  
Noncoding Rna ◽  
Dna Methyltransferase ◽  
Large Scale ◽  
Cpg Island ◽  
Methylation Status ◽  
Neuroblastoma Cells ◽  
Regulatory Elements ◽  
Protein Coding ◽  
Non Coding Rna

Many intergenic long noncoding RNA (lncRNA) loci regulate the expression of adjacent protein coding genes. Less clear is whether intergenic lncRNAs commonly regulate transcription by modulating chromatin at genomically distant loci. Here, we report both genomically local and distal RNA-dependent roles of Dali, a conserved central nervous system expressed intergenic lncRNA. Dali is transcribed downstream of the Pou3f3 transcription factor gene and its depletion disrupts the differentiation of neuroblastoma cells. Locally, Dali transcript regulates transcription of the Pou3f3 locus. Distally, it preferentially targets active promoters and regulates expression of neural differentiation genes, in part through physical association with the POU3F3 protein. Dali interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates DNA methylation status of CpG island-associated promoters in trans. These results demonstrate, for the first time, that a single intergenic lncRNA controls the activity and methylation of genomically distal regulatory elements to modulate large-scale transcriptional programmes.

scholarly journals Exploring the overlap between rheumatoid arthritis susceptibility loci and long non-coding RNA annotations

2019 ◽  
Author(s):  
James Ding ◽  
Chenfu Shi ◽  
John Bowes ◽  
Stephen Eyre ◽  
Gisela Orozco
Keyword(s):  
Rheumatoid Arthritis ◽  
Complex Diseases ◽  
Cell Types ◽  
Protein Coding ◽  
Major Mechanism ◽  
Coding Regions ◽  
Functional Characterisation ◽  
Non Coding Rna ◽  
Significant Enrichment ◽  
Local Enrichment

ABSTRACTWhilst susceptibility variants for many complex diseases, such as rheumatoid arthritis (RA), have been well characterised, the mechanism by which risk is mediated is still unclear for many loci. This is especially true for the majority of variants that do not affect protein-coding regions. lncRNA represent a group of molecules that have been shown to be enriched amongst variants associated with RA and other complex diseases, compared to random variants. In order to establish to what degree direct disruption of lncRNA may represent a potential mechanism for mediating RA susceptibility, we chose to further explore this overlap. By testing the ability of annotated features to improve a model of disease susceptibility, we were able to demonstrate a local enrichment of enhancers from immune-relevant cell types amongst RA susceptibility variants (log2 enrichment 3.40). This was not possible for lncRNA annotations in general, however a small, but significant enrichment was observed for immune-enriched lncRNA (log2 enrichment 0.867002). This enrichment was no longer apparent when the model was conditioned on immune-relevant enhancers (log2 enrichment -0.372734), suggesting that direct disruption of lncRNA sequence, independent of enhancer disruption, does not represent a major mechanism by which susceptibility to complex diseases is mediated. Furthermore, we demonstrated that, in keeping with general lncRNA characteristics, immune-enriched lncRNA are expressed at low levels that may not be amenable to functional characterisation.

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 Community structure of non-coding RNA interaction network

2013 ◽  
Vol 10 (2) ◽  
pp. 24-34 ◽  
Author(s):  
Jose C. Nacher
Keyword(s):  
Community Structure ◽  
Current Knowledge ◽  
Scaling Law ◽  
Interaction Network ◽  
Bipartite Network ◽  
Protein Coding ◽  
Technological Advances ◽  
Non Coding Rna ◽  
Genetic Information Processing ◽  
Rna Interaction

Summary Rapid technological advances have shown that the ratio of non-protein coding genes rises to 98.5% in humans, suggesting that current knowledge on genetic information processing might be largely incomplete. It implies that protein-coding sequences only represent a small fraction of cellular transcriptional information. Here, we examine the community structure of the network defined by functional interactions between noncoding RNAs (ncRNAs) and proteins related bio-macrolecules (PRMs) using a two-fold approach: modularity in bipartite network and k-clique community detection. First, the high modularity scores as well as the distribution of community sizes showing a scaling-law revealed manifestly non-random features. Second, the k-clique sub-graphs and overlaps show that the identified communities of the ncRNA molecules of H. sapiens can potentially be associated with certain functions. These findings highlight the complex modular structure of ncRNA interactions and its possible regulatory roles in the cell.

scholarly journals A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1048
Author(s):  
Ilse Meerschaut ◽  
Sarah Vergult ◽  
Annelies Dheedene ◽  
Björn Menten ◽  
Katya De Groote ◽  
...  
Keyword(s):  
Copy Number ◽  
Congenital Heart ◽  
Heart Defects ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Related Gene ◽  
Protein Coding ◽  
Gene Enhancer ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.

scholarly journals ENDOGENOUS RETROVIRUSES AS GENETIC MODULES THAT SHAPE THE GENOME REGULATORY NETWORKS DURING EVOLUTION

2018 ◽  
Keyword(s):  
Regulatory Networks ◽  
Gene Activation ◽  
Cell Types ◽  
Regulatory Elements ◽  
Endogenous Retroviruses ◽  
Protein Coding ◽  
Transcriptional Enhancers ◽  
Wide Range ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

Endogenous retroviruses (ERV) are the descendants of exogenous retroviruses that integrated into the germ cells genome, fixed and became inheritable. ERVs have evolved transcriptional enhancers and promoters that allow their replication in a wide range of tissue. Because ERVs comprise the regulatory elements it could be assume that ERVs capable to shape and reshape genomic regulatory networks by inserting their promoters and enhancers in new genomic loci upon retrotransposition. Thus retroransposition events can build new regulatory regions and lead to a new pattern of gene activation in the cell. In this review we summarize evidence which revealed that ERVs provide a plethora of novel gene regulatory elements, including tissue specific promoters and enhancers for protein-coding genes or long noncoding RNAs in a wide range of cell types. The accumulated findings support the hypothesis that the ERVs have rewired the gene regulatory networks and act as a major source of genomic regulatory innovation during evolution.

scholarly journals Paleozoic Protein Fossils Illuminate the Evolution of Vertebrate Genomes and Transposable Elements

2021 ◽  
Author(s):  
Martin C Frith
Keyword(s):  
Transposable Elements ◽  
Common Ancestor ◽  
Regulatory Elements ◽  
Regulatory Function ◽  
Last Common Ancestor ◽  
Protein Coding ◽  
New Genes ◽  
Gene Regulatory ◽  
Host Genes ◽  
The Way

Genomes hold a treasure trove of protein fossils: fragments of formerly protein-coding DNA, which mainly come from transposable elements (TEs) or host genes. These fossils reveal ancient evolution of TEs and genomes, and many fossils have been exapted to perform diverse functions important for the host's fitness. However, old and highly-degraded fossils are hard to identify, and standard methods (e.g. BLAST) are not optimized for this task. Here, a recently optimized method is used to find protein fossils in vertebrate genomes. It finds Paleozoic fossils predating the amphibian/amniote divergence from most major TE categories, including virus-related Polinton and Gypsy elements. It finds 10 fossils in the human genome (8 from TEs and 2 from host genes) that predate the last common ancestor of all jawed vertebrates, probably from the Ordovician period. It also finds types of transposon and retrotransposon not found in human before. These fossils have extreme sequence conservation, indicating exaptation: some have evidence of gene-regulatory function, and they tend to lie nearest to developmental genes. Some ancient fossils suggest "genome tectonics", where two fragments of one TE have drifted apart by up to megabases, possibly explaining gene deserts and large introns. This paints a picture of great TE diversity in our aquatic ancestors, with patchy TE inheritance by later vertebrates, producing new genes and regulatory elements on the way. Host-gene fossils too have contributed anciently-conserved DNA segments. This paves the way to further studies of ancient protein fossils.

The origins and evolutionary history of human non-coding RNA regulatory networks

2017 ◽  
Vol 15 (02) ◽  
pp. 1750005 ◽  
Author(s):  
Masih Sherafatian ◽  
Seyed Javad Mowla
Keyword(s):  
Cell Cycle ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Evolutionary History ◽  
Regulatory Function ◽  
Protein Coding ◽  
Evolutionary Pattern ◽  
Non Coding Rna ◽  
History Of ◽  
Non Coding Rnas

The evolutionary history and origin of the regulatory function of animal non-coding RNAs are not well understood. Lack of conservation of long non-coding RNAs and small sizes of microRNAs has been major obstacles in their phylogenetic analysis. In this study, we tried to shed more light on the evolution of ncRNA regulatory networks by changing our phylogenetic strategy to focus on the evolutionary pattern of their protein coding targets. We used available target databases of miRNAs and lncRNAs to find their protein coding targets in human. We were able to recognize evolutionary hallmarks of ncRNA targets by phylostratigraphic analysis. We found the conventional 3′-UTR and lesser known 5′-UTR targets of miRNAs to be enriched at three consecutive phylostrata. Firstly, in eukaryata phylostratum corresponding to the emergence of miRNAs, our study revealed that miRNA targets function primarily in cell cycle processes. Moreover, the same overrepresentation of the targets observed in the next two consecutive phylostrata, opisthokonta and eumetazoa, corresponded to the expansion periods of miRNAs in animals evolution. Coding sequence targets of miRNAs showed a delayed rise at opisthokonta phylostratum, compared to the 3′ and 5′ UTR targets of miRNAs. LncRNA regulatory network was the latest to evolve at eumetazoa.

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.

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