Enhancer RNAs: transcriptional regulators and workmates of NamiRNAs in myogenesis

AbstractmiRNAs are well known to be gene repressors. A newly identified class of miRNAs termed nuclear activating miRNAs (NamiRNAs), transcribed from miRNA loci that exhibit enhancer features, promote gene expression via binding to the promoter and enhancer marker regions of the target genes. Meanwhile, activated enhancers produce endogenous non-coding RNAs (named enhancer RNAs, eRNAs) to activate gene expression. During chromatin looping, transcribed eRNAs interact with NamiRNAs through enhancer-promoter interaction to perform similar functions. Here, we review the functional differences and similarities between eRNAs and NamiRNAs in myogenesis and disease. We also propose models demonstrating their mutual mechanism and function. We conclude that eRNAs are active molecules, transcriptional regulators, and partners of NamiRNAs, rather than mere RNAs produced during enhancer activation.

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Targeting riboswitches with synthetic small RNAs for metabolic engineering

10.1101/2021.06.21.449321 ◽

2021 ◽

Author(s):

Milca Rachel da Costa Ribeiro Lins ◽

Laura Araujo da Silva Amorim ◽

Graciely Gomes Correa ◽

Bruno Willian Picao ◽

Matthias Mack ◽

...

Keyword(s):

Gene Expression ◽

Rational Design ◽

Regulation Of Gene Expression ◽

Cellular Systems ◽

Producer Strain ◽

Natural Systems ◽

Single Genome ◽

Non Coding Rnas ◽

And Function ◽

Activate Gene

Our growing knowledge of the diversity of non-coding RNAs in natural systems and our deepening knowledge of RNA folding and function have fomented the rational design of RNA regulators. Based on that knowledge, we designed and implemented a small RNA (sRNA) tool to target bacterial riboswitches and activate gene expression. The synthetic sRNA is suitable for the regulation of gene expression both in cell-free and in cellular systems. It targets riboswitches to promote the antitermination folding regardless the cognate metabolite concentration. Therefore, it prevents transcription termination increasing gene expression up to 103-fold. We successfully used sRNA arrays for multiplex targeting of riboswitches. Finally, we used the synthetic sRNA to engineer an improved riboflavin producer strain. The easiness to design and construct, and the fact that the riboswitch-targeting sRNA works as a single genome copy, make it an attractive tool for engineering industrial metabolite-producing strains.

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Evolutionary Analysis of Transcriptional Regulation Mediated by Cdx2 in Rodents

10.21203/rs.3.rs-511600/v1 ◽

2021 ◽

Author(s):

Weizheng Liang ◽

Guipeng Li ◽

Huanhuan Cui ◽

Yukai Wang ◽

Wencheng Wei ◽

...

Keyword(s):

Gene Expression ◽

Amino Acid ◽

Dna Binding ◽

Target Genes ◽

Embryonic Stem ◽

Regulatory Elements ◽

Evolutionary Analysis ◽

Protein Sequence Analysis ◽

Functional Differences ◽

Transcriptional Effect

Abstract Background: Differences in gene expression, which arises from divergence in cis-regulatory elements or alterations in transcription factors (TFs) binding specificity, are one of the most important causes of phenotypic diversity during evolution. On one hand, changes in the cis-elements located in the vicinity of target genes affect TF binding and/or local chromatin environment, thereby modulating gene expression in one-to-one manner. On the other hand, alterations in trans-factors influence the expression of their target genes in a more pleiotropic fashion. Although evolution of amino acid sequences is much slower than that of non-coding regulatory elements, particularly for the TF DNA binding domains (DBD)， it is still possible that changes in TF-DBD might have the potential to drive large phenotypic changes if the resulting effects have a net positive effect on the organism’s fitness. If so, species-specific changes in TF-DBD might be positively selected. So far, however, this possibility has been largely unexplored.Results: By protein sequence analysis, we observed high sequence conservation in the DNA binding domain (DBD) of the transcription factor Cdx2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells (RMES) to study the cis effects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent.Conclusions: There were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Moreover, Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent.

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xB elements strongly activate gene expression in non-lymphoid cells and function synergistically with NF1 elements

Nucleic Acids Research ◽

10.1093/nar/17.20.8197 ◽

1989 ◽

Vol 17 (20) ◽

pp. 8197-8206 ◽

Cited By ~ 1

Author(s):

Lothar Henninghausen ◽

Priscilla A. Furth ◽

Chirstoph W. Pittius

Keyword(s):

Gene Expression ◽

Lymphoid Cells ◽

And Function ◽

Activate Gene

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An Arabidopsis gene expression predictor enables inference of transcriptional regulators

10.1101/2020.04.07.029413 ◽

2020 ◽

Author(s):

Haiying Geng ◽

Meng Wang ◽

Jiazhen Gong ◽

Yupu Xu ◽

Shisong Ma

Keyword(s):

Gene Expression ◽

Lateral Root ◽

Secondary Cell Wall ◽

Target Genes ◽

Gene Expression Regulation ◽

Transcriptional Regulators ◽

Endoplasmic Reticulum Stress Response ◽

Rna Seq ◽

Average Correlation ◽

Cell Wall Development

ABSTRACTGene expression regulation by transcription factors (TF) has long been studied, but no model exists yet that can accurately predict transcriptome profiles based on TF activities. We have constructed a universal predictor for Arabidopsis to predict the expression of 28192 non-TF genes using 1678 TFs. Applied to bulk RNA-Seq samples from diverse tissues, the predictor produced accurate predicted transcriptomes correlating well with actual expression, with average correlation coefficient of 0.986. Having recapitulated the quantitative relationships between TFs and target genes, the predictor further enabled downstream inference of TF regulators for genes and pathways, i.e. those involved in suberin, flavonoid, glucosinolate metabolism, lateral root, xylem, secondary cell wall development, and endoplasmic reticulum stress response. Our predictor provides an innovative approach to study transcriptional regulation.

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Multiple transcription factors co-regulate the Mycobacterium tuberculosis adaptation response to vitamin C

BMC Genomics ◽

10.1186/s12864-019-6190-3 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Malobi Nandi ◽

Kriti Sikri ◽

Neha Chaudhary ◽

Shekhar Chintamani Mande ◽

Ravi Datta Sharma ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Mycobacterium Tuberculosis ◽

Vitamin C ◽

Large Scale ◽

Target Genes ◽

Transcriptional Regulatory Network ◽

Transcriptional Regulators ◽

Transcriptional Regulatory ◽

Modulation Of Gene Expression

Abstract Background Latent tuberculosis infection is attributed in part to the existence of Mycobacterium tuberculosis in a persistent non-replicating dormant state that is associated with tolerance to host defence mechanisms and antibiotics. We have recently reported that vitamin C treatment of M. tuberculosis triggers the rapid development of bacterial dormancy. Temporal genome-wide transcriptome analysis has revealed that vitamin C-induced dormancy is associated with a large-scale modulation of gene expression in M. tuberculosis. Results An updated transcriptional regulatory network of M.tuberculosis (Mtb-TRN) consisting of 178 regulators and 3432 target genes was constructed. The temporal transcriptome data generated in response to vitamin C was overlaid on the Mtb-TRN (vitamin C Mtb-TRN) to derive insights into the transcriptional regulatory features in vitamin C-adapted bacteria. Statistical analysis using Fisher’s exact test predicted that 56 regulators play a central role in modulating genes which are involved in growth, respiration, metabolism and repair functions. Rv0348, DevR, MprA and RegX3 participate in a core temporal regulatory response during 0.25 h to 8 h of vitamin C treatment. Temporal network analysis further revealed Rv0348 to be the most prominent hub regulator with maximum interactions in the vitamin C Mtb-TRN. Experimental analysis revealed that Rv0348 and DevR proteins interact with each other, and this interaction results in an enhanced binding of DevR to its target promoter. These findings, together with the enhanced expression of devR and Rv0348 transcriptional regulators, indicate a second-level regulation of target genes through transcription factor- transcription factor interactions. Conclusions Temporal regulatory analysis of the vitamin C Mtb-TRN revealed that there is involvement of multiple regulators during bacterial adaptation to dormancy. Our findings suggest that Rv0348 is a prominent hub regulator in the vitamin C model and large-scale modulation of gene expression is achieved through interactions of Rv0348 with other transcriptional regulators.

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The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities

Molecular Cancer ◽

10.1186/s12943-020-01263-w ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Paz Nombela ◽

Borja Miguel-López ◽

Sandra Blanco

Keyword(s):

Gene Expression ◽

Rna Processing ◽

Therapeutic Potential ◽

Biological Processes ◽

Rna Modifications ◽

Non Coding Rna ◽

Non Coding Rnas ◽

And Function ◽

Made In

AbstractRNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N6-methyladenosine (m6A), 5-methylcytosine (m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.

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Identification of Target Genes of an Erythroid Transcription Factor Complex Containing SCL (TAL1).

Blood ◽

10.1182/blood.v110.11.4068.4068 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4068-4068 ◽

Cited By ~ 1

Author(s):

Johanna H. Jim ◽

Pawandeep Dhami ◽

Amanda King ◽

Jonathan Cooper ◽

Dave Vetrie

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Cell Line ◽

K562 Cell ◽

Target Genes ◽

K562 Cell Line ◽

Acute Lymphocytic Leukaemia ◽

Novel Target ◽

And Function ◽

Erythroid Development

Abstract Haematopoiesis is the process whereby haematopoietic stem cells give rise to mature blood cell lineages. The SCL (TAL1) gene, originally identified by chromosomal translocations associated with T-cell acute lymphocytic leukaemia, encodes a key transcription factor (TF) which is expressed in various blood lineages and is essential for haematopoietic development. It has been shown that the SCL protein forms a multi-protein complex during erythroid development with other TFs (GATA1, E2A, LDB1, and LMO2) which binds to a sequence-specific motif to regulate the expression of glycophorin A and c-kit. We have used two complementary approaches to identify novel target genes regulated by this TF complex during erythroid development. In the first approach, we have transfected short interfering RNAs (siRNAs) into the K562 cell line to knockdown transiently the TFs of the erythroid complex. For all members of the complex, a knockdown efficiency of at least 70% was confirmed at the mRNA and protein level within 48 hours after transfection. The consequences of the knockdown at the level of gene expression were observed using Affymetrix GeneChips in order to identify downstream events associated with the erythroid complex in transcriptional programmes. In the second approach, chromatin immunoprecipitation (ChIP) was performed for each member of the complex in the K562 cell line and the ChIP material hybridised to a human transcription factor promoter microarray. A number of novel target genes for the SCL erythroid complex have been identified and verified independently using both approaches. Our data shows that members of the erythroid complex are involved in auto-regulation and regulate genes which control chromatin structure and function. These findings demonstrate that the expression of this TF complex is tightly controlled and point to an important role for it in orchestrating fundamental biological processes which have profound effects on gene expression in erythroid development.

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Identification and function of long non-coding RNAs

Essays in Biochemistry ◽

10.1042/bse0540113 ◽

2013 ◽

Vol 54 ◽

pp. 113-126 ◽

Cited By ~ 33

Author(s):

Robert S. Young ◽

Chris P. Ponting

Keyword(s):

Gene Expression ◽

Experimental Investigation ◽

Eukaryotic Cells ◽

Functional Roles ◽

New Class ◽

Biological Relevance ◽

Genome Wide ◽

Non Coding Rnas ◽

And Function ◽

Different Levels

It is now clear that eukaryotic cells produce many thousands of non-coding RNAs. The least well-studied of these are longer than 200 nt and are known as lncRNAs (long non-coding RNAs). These loci are of particular interest as their biological relevance remains uncertain. Sequencing projects have identified thousands of these loci in a variety of species, from flies to humans. Genome-wide scans for functionality, such as evolutionary and expression analyses, suggest that many of these molecules have functional roles to play in the cell. Nevertheless, only a handful of lncRNAs have been experimentally investigated, and most of these appear to possess roles in regulating gene expression at a variety of different levels. Several lncRNAs have also been implicated in cancer. This evidence suggests that lncRNAs represent a new class of non-coding gene whose importance should become clearer upon further experimental investigation.

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Global Transcriptome Analysis Reveals That Poly(ADP-Ribose) Polymerase 1 Regulates Gene Expression through EZH2

Molecular and Cellular Biology ◽

10.1128/mcb.00635-15 ◽

2015 ◽

Vol 35 (23) ◽

pp. 3934-3944 ◽

Cited By ~ 20

Author(s):

Kayla A. Martin ◽

Matteo Cesaroni ◽

Michael F. Denny ◽

Lena N. Lupey ◽

Italo Tempera

Keyword(s):

Gene Expression ◽

Gene Silencing ◽

Posttranslational Modifications ◽

Target Genes ◽

Global Gene Expression ◽

Parp Inhibition ◽

Direct Role ◽

Polycomb Repressive Complex 2 ◽

And Function

Posttranslational modifications, such as poly(ADP-ribosyl)ation (PARylation), regulate chromatin-modifying enzymes, ultimately affecting gene expression. This study explores the role of poly(ADP-ribose) polymerase (PARP) on global gene expression in a lymphoblastoid B cell line. We found that inhibition of PARP catalytic activity with olaparib resulted in global gene deregulation, affecting approximately 11% of the genes expressed. Gene ontology analysis revealed that PARP could exert these effects through transcription factors and chromatin-remodeling enzymes, including the polycomb repressive complex 2 (PRC2) member EZH2. EZH2 mediates the trimethylation of histone H3 at lysine 27 (H3K27me3), a modification associated with chromatin compaction and gene silencing. Both pharmacological inhibition of PARP and knockdown of PARP1 induced the expression of EZH2, which resulted in increased global H3K27me3. Chromatin immunoprecipitation confirmed that PARP1 inhibition led to H3K27me3 deposition at EZH2 target genes, which resulted in gene silencing. Moreover, increased EZH2 expression is attributed to the loss of the occupancy of the transcription repressor E2F4 at the EZH2 promoter following PARP inhibition. Together, these data show that PARP plays an important role in global gene regulation and identifies for the first time a direct role of PARP1 in regulating the expression and function of EZH2.

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Identifying long non-coding RNAs and characterizing their functional roles in swine mammary gland from colostrogenesis to lactogenesis

10.1101/2021.01.17.426976 ◽

2021 ◽

Author(s):

Lijun Shi ◽

Longchao Zhang ◽

Ligang Wang ◽

Xin Liu ◽

Hongmei Gao ◽

...

Keyword(s):

Mammary Gland ◽

Expression Pattern ◽

Target Genes ◽

Milk Composition ◽

Integrated Analysis ◽

Functional Roles ◽

Prediction Function ◽

Non Coding Rnas ◽

And Function ◽

Gland Development

AbstractLong non-coding RNAs (lncRNAs) play important regulatory roles in milk biological processes. While, little is known about the identification and function of swine lncRNAs in response to mammary gland development. Here, we identified 286 differentially expressed (DE) lncRNAs in mammary gland at different stages from 14 days prior to (-) parturition to day 1 after (+) parturition using the published RNA-seq data. The expression pattern of these DE lncRNAs was examined, and most of lncRNAs expressions were strongly changed from Day −2 to Day +1. Functional annotation revealed that the DE lncRNAs were mainly involved in the mammary gland developing, lactation developing, milk composition metabolism and colostrum function. By performing the weighted gene co-expression network analysis (WGCNA), we identified 7 out of 12 lncRNA-mRNA modules, including 35 lncRNAs and 319 mRNAs, which were highly associated with the mammary gland at Day −14, Day −2 and Day +1. Integrated analysis of the DE lncRNAs expression pattern examination, targets prediction, function annotation and WGCNA suggested that 18 lncRNAs (such as, XLOC_020627, ENSSSCG00000051193, XLOC_025150, ENSSSCG00000042618, XLOC_963181, ENSSSCG00000051701, XLOC_018030, and XLOC_025146) and their 20 target genes (such as, ACTN4, ADCY1, CSN3, SMO, CSN2, PRKAG2, FIBCD1, and GALNT7), were considered as the promising candidates for swine parturition and colostrum occurrence processes. Our research provided the insights into lncRNA profiles and their regulating mechanisms from colostrogenesis to lactogenesis in swine.

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