Insights into Enhancer RNAs: Biogenesis and Emerging Role in Brain Diseases

2021 ◽  
pp. 107385842110468
Author(s):  
Yuxin Shen ◽  
Zhengyi Huang ◽  
Ruiqing Yang ◽  
Yunlong Chen ◽  
Qiang Wang ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Small Proportion ◽  
Target Genes ◽  
Noncoding Rnas ◽  
Histone Mark ◽  
Brain Diseases ◽  
Enhancer Activity ◽  
Cis Acting ◽  
High Level ◽  
Classification Function

Enhancers are cis-acting elements that control the transcription of target genes and are transcribed into a class of noncoding RNAs (ncRNAs) termed enhancer RNAs (eRNAs). eRNAs have shorter half-lives than mRNAs and long noncoding RNAs; however, the frequency of transcription of eRNAs is close to that of mRNAs. eRNA expression is associated with a high level of histone mark H3K27ac and a low level of H3K27me3. Although eRNAs only account for a small proportion of ncRNAs, their functions are important. eRNAs can not only increase enhancer activity by promoting the formation of enhancer-promoter loops but also regulate transcriptional activation. Increasing numbers of studies have found that eRNAs play an important role in the occurrence and development of brain diseases; however, further research into eRNAs is required. This review discusses the concept, characteristics, classification, function, and potential roles of eRNAs in brain diseases.

scholarly journals Interdependent Recruitment of SAGA and Srb Mediator by Transcriptional Activator Gcn4p

2005 ◽  
Vol 25 (9) ◽  
pp. 3461-3474 ◽  
Author(s):  
Hongfang Qiu ◽  
Cuihua Hu ◽  
Fan Zhang ◽  
Gwo Jiunn Hwang ◽  
Mark J. Swanson ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Wild Type ◽  
General Transcription Factors ◽  
Tata Element ◽  
High Level ◽  
Target Promoters ◽  
Activation Sequence

ABSTRACT Transcriptional activation by Gcn4p is enhanced by the coactivators SWI/SNF, SAGA, and Srb mediator, which stimulate recruitment of TATA binding protein (TBP) and polymerase II to target promoters. We show that wild-type recruitment of SAGA by Gcn4p is dependent on mediator but independent of SWI/SNF function at three different promoters. Recruitment of mediator is also independent of SWI/SNF but is enhanced by SAGA at a subset of Gcn4p target genes. Recruitment of all three coactivators to ARG1 is independent of the TATA element and preinitiation complex formation, whereas efficient recruitment of the general transcription factors requires the TATA box. We propose an activation pathway involving interdependent recruitment of SAGA and Srb mediator to the upstream activation sequence, enabling SWI/SNF recruitment and the binding of TBP and other general factors to the promoter. We also found that high-level recruitment of Tra1p and other SAGA subunits is independent of the Ada2p/Ada3p/Gcn5p histone acetyltransferase module but requires Spt3p in addition to subunits required for SAGA integrity. Thus, while Tra1p can bind directly to Gcn4p in vitro, it requires other SAGA subunits for efficient recruitment in vivo.

scholarly journals Transcription Factor Pip Can Enhance DNA Binding by E47, Leading to Transcriptional Synergy Involving Multiple Protein Domains

1998 ◽  
Vol 18 (8) ◽  
pp. 4639-4650 ◽  
Author(s):  
Sujatha Nagulapalli ◽  
Michael L. Atchison
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Conformational Change ◽  
Transcriptional Activation ◽  
Regulatory Sequences ◽  
Enhancer Activity ◽  
Multiple Protein ◽  
Transactivation Potential ◽  
Potential Part ◽  
High Level

ABSTRACT The transcription factors E2A (E12/E47) and Pip are both required for normal B-cell development. Each protein binds to regulatory sequences within various immunoglobulin enhancer elements. Activity of E2A proteins can be regulated by interactions with other proteins which influence their DNA binding or activation potential. Similarly, Pip function can be influenced by interaction with the protein PU.1, which can recruit Pip to bind to DNA. We show here that a previously unidentified Pip binding site resides adjacent to the E2A binding site within the immunoglobulin κ 3′ enhancer. Both of these binding sites are crucial for high-level enhancer activity. We found that E47 and Pip can functionally interact to generate a very potent 100-fold transcriptional synergy. Through a series of mutagenesis experiments, we identified the Pip sequences necessary for transcriptional activation and for synergy with E47. Two synergy domains (residues 140 to 207 and 300 to 420) in addition to the Pip DNA binding domain (residues 1 to 134) are required for maximal synergy with E47. We also identified a Pip domain (residues 207 to 300) that appears to mask Pip transactivation potential. Part of the synergy mechanism between E47 and Pip appears to involve the ability of Pip to increase DNA binding by E47, perhaps by inducing a conformational change in the E47 protein. E47 may also induce a conformational change in Pip which unmasks sequences important for transcriptional activity. Based upon our results, we propose a model for E47-Pip transcriptional synergy.

VX-809/661 Correction of F508del-CFTR Rescue Nrf2 Dysfunction In CF Airway Epithelia: Supplemental Figures

2019 ◽  
Author(s):  
Dana C Borcherding ◽  
Songbai Lin ◽  
Matthew Siefert ◽  
John Brewington ◽  
Scott Plafker ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Redox Balance ◽  
Proximity Ligation Assay ◽  
Related Factor ◽  
Airway Epithelia ◽  
Channel Function ◽  
Bronchial Epithelia ◽  
High Level

Cystic Fibrosis (CF) is a multi-organ progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel, including in airway epithelia. Previously, we identified a significant dysfunction in CF cells of the transcription factor nuclear-factor-E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report the discovery of an interaction and colocalization of Nrf2 and CFTR in non-CF human primary bronchial epithelia by Proximity Ligation Assay, immunoprecipitation, and immunofluorescence, which is diminished in CF human primary bronchial epithelia, and rescued with VX-809 or VX-661 treatment for 48-72 hr. In primary CF cells, F508del-CFTR correctors induce Nrf2 nuclear localization, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Diminished Nrf2 activity and colocalization with F508del-CFTR is also exhibited in mutant mice. Correction of Nrf2 by VX-809/VX-661 is dependent on sufficient correction of F508del and is blocked by inhibition of corrected channel function, or high-level shRNA knockdown of F508del-CFTR. Finally, partial CFTR knockdown, insufficient to decrease channel function, does not inhibit Nrf2 activity, further establishing the importance of CFTR function. Our findings demonstrate, for the first time, that CFTR and Nrf2 interact, and that VX-809/VX-661 correction of CFTR can correct Nrf2 dysfunction in CF.  

scholarly journals Hepatocyte nuclear factor 1alpha gene inactivation impairs chromatin remodeling and demethylation of the phenylalanine hydroxylase gene.

1997 ◽  
Vol 17 (9) ◽  
pp. 4948-4956 ◽  
Author(s):  
M Pontoglio ◽  
D M Faust ◽  
A Doyen ◽  
M Yaniv ◽  
M C Weiss
Keyword(s):  
Chromatin Structure ◽  
Target Genes ◽  
Phenylalanine Hydroxylase ◽  
Dnase I ◽  
Micrococcal Nuclease ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Enhancer Activity ◽  
Cis Acting ◽  
Pah Gene

Hepatocyte nuclear factor 1 alpha (HNF1alpha) is a homeoprotein that is expressed in the liver, kidney, pancreas, and digestive tract. Its inactivation in mouse resulted in decreased transcription of known target genes such as albumin and alpha1-antitrypsin. In contrast, the phenylalanine hydroxylase (PAH) gene was totally silent and unresponsive to normal inducers like glucocorticoids and cyclic AMP in the liver. DNase I and micrococcal nuclease digestion of liver nuclei showed that HNF1alpha inactivation had drastic effects on the chromatin structure of the PAH regulatory regions. Three DNase I-hypersensitive sites (HSSI, HSSII, and HSSIII), typical of the actively transcribed PAH gene, were undetectable in liver from HNF1alpha-deficient animals. Both HSSII and HSSIII elements harbor HNF1 sites, but only the latter has detectable enhancer activity in transient-transfection assays. In addition, the PAH promoter in livers of HNF1alpha-deficient animals was methylated. These results suggest that HNF1alpha could activate transcription through two mechanisms. One implies participation in the recruitment of the general transcription machinery to the promoter, and the second involves the remodeling of chromatin structure and demethylation that would allow transcription factors to interact with their cognate cis-acting elements.

scholarly journals Genome-Wide Identification of Barley Long Noncoding RNAs and Analysis of Their Regulatory Interactions during Shoot and Grain Development

2021 ◽  
Vol 22 (10) ◽  
pp. 5087
Author(s):  
Sebastian Gasparis ◽  
Mateusz Przyborowski ◽  
Anna Nadolska-Orczyk
Keyword(s):  
Target Genes ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Shoot Apices ◽  
Protein Coding ◽  
Cis Acting ◽  
Rna Molecules ◽  
Functional Studies ◽  
Potential Target ◽  
Genome Wide

Long noncoding RNAs (lncRNAs) are a class of RNA molecules with gene regulatory functions in plant development and the stress response. Although the number of lncRNAs identified in plants is rapidly increasing, very little is known about their role in barley development. In this study, we performed global identification of barley lncRNAs based on 53 RNAseq libraries derived from nine different barley tissues and organs. In total, 17,250 lncRNAs derived from 10,883 loci were identified, including 8954 novel lncRNAs. Differential expression of lncRNAs was observed in the developing shoot apices and grains, the two organs that have a direct influence on the final yield. The regulatory interaction of differentially expressed lncRNAs with the potential target genes was evaluated. We identified 176 cis-acting lncRNAs in shoot apices and 424 in grains, while the number of trans-acting lncRNAs in these organs was 1736 and 540, respectively. The potential target protein-coding genes were identified, and their biological function was annotated using MapMan ontology. This is the first insight into the roles of lncRNAs in barley development on the genome-wide scale, and our results provide a solid background for future functional studies.

scholarly journals A complex regulatory element from the yeast gene ENO2 modulates GCR1-dependent transcriptional activation

1993 ◽  
Vol 13 (4) ◽  
pp. 2623-2633
Author(s):  
C E Willett ◽  
C M Gelfman ◽  
M J Holland
Keyword(s):  
Binding Site ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Regulatory Element ◽  
Enhancer Element ◽  
Cis Acting ◽  
Genes Encoding ◽  
High Level ◽  
Yeast Genes ◽  
Yeast Enolase

The GCR1 gene product is required for maximal transcription of many yeast genes including genes encoding glycolytic enzymes. Transcription of the yeast enolase gene ENO2 is reduced 50-fold in strains carrying a gcr1 null mutation. cis-acting sequences that are sufficient for GCR1-dependent regulation of ENO2 expression were identified by using an enhancerless CYC1 promoter which is not normally dependent on GCR1 for expression. A 60-bp ENO2 sequence that was sufficient to provide high-level, GCR1-dependent transcriptional activation of the CYC1 promoter was identified. This 60-bp element could be subdivided into a 30-bp sequence containing a novel RAP1-binding site and a GCR1-binding site which did not activate CYC1 transcription and a 30-bp sequence containing a novel enhancer element that conferred moderate levels of GCR1-independent transcriptional activation. The 60-bp CGCR1-dependent upstream activator sequence is located immediately downstream from previously mapped overlapping binding sites for the regulatory proteins ABFI and RAP1. Evidence is presented that the overlapping ABFI- and RAP1-binding sites function together with sequences that bind GCR1 and RAP1 to stage transcriptional activation of ENO2 expression.

A novel cis-acting DNA element required for a high level of inducible expression of the rat P-450c gene

1990 ◽  
Vol 10 (4) ◽  
pp. 1470-1475
Author(s):  
A Yanagida ◽  
K Sogawa ◽  
K I Yasumoto ◽  
Y Fujii-Kuriyama
Keyword(s):  
Regulatory Element ◽  
Consensus Sequence ◽  
Inducible Expression ◽  
Recognition Sequence ◽  
Mobility Shift ◽  
Enhancer Activity ◽  
Cis Acting ◽  
Tata Sequence ◽  
Gel Mobility Shift ◽  
High Level

A novel cis-acting regulatory element (designated BTE for basic transcription element) was found in the region proximal to the TATA sequence of the P-450c gene by the use of deletion mutations. This DNA element is considered to be involved in the basic transcription of the gene and does not show distinct enhancer activity in itself. Together with the XRE sequence (A. Fujisawa-Sehara, K. Sogawa, M. Yamane, and Y. Fujii-Kuriyama, Nucleic Acids Res. 15:4179-4191, 1987), however, this sequence is required for a high inducible expression of the P-450c gene in response to xenobiotic inducers. The BTE sequence contained the GC box consensus sequence and half of the NF-1-binding consensus or CAT box sequence, but their synthetic oligonucleotides, used as competitors in the gel mobility shift assays, did not compete with the BTE sequence for the binding protein, suggesting that the BTE sequence functions as a different recognition sequence from that for Sp1 or NF-1. Analogous sequences to BTE are found in the region proximal to the TATA sequence of other genes, especially other P-450 genes with different modes of regulation, suggesting that the BTE sequence plays a common regulatory role in basic transcription of genes including a group of the P-450 superfamily. The ubiquitous distribution of nuclear factor(s) binding to this element supports this suggestion.

scholarly journals Cis-acting lnc-eRNA SEELA directly binds histone H4 to promote histone recognition and leukemia progression

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ke Fang ◽  
Wei Huang ◽  
Yu-Meng Sun ◽  
Tian-Qi Chen ◽  
Zhan-Cheng Zeng ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Cancer Metabolism ◽  
Chromosomal Translocation ◽  
Underlying Mechanism ◽  
Histone H4 ◽  
Transcription Control ◽  
Hoxa Cluster ◽  
Enhancer Activity ◽  
Cis Acting ◽  
Cancer Initiation

Abstract Background Long noncoding enhancer RNAs (lnc-eRNAs) are a subset of stable eRNAs identified from annotated lncRNAs. They might act as enhancer activity-related therapeutic targets in cancer. However, the underlying mechanism of epigenetic activation and their function in cancer initiation and progression remain largely unknown. Results We identify a set of lncRNAs as lnc-eRNAs according to the epigenetic signatures of enhancers. We show that these lnc-eRNAs are broadly activated in MLL-rearranged leukemia (MLL leukemia), an aggressive leukemia caused by a chromosomal translocation, through a mechanism by which the HOXA cluster initiates enhancer activity, and the epigenetic reader BRD4 cooperates with the coregulator MLL fusion oncoprotein to induce transcriptional activation. To demonstrate the functional roles of lnc-eRNAs, two newly identified lnc-eRNAs transcribed from the SEELA eRNA cluster (SEELA), SEELA1 and SEELA2, are chosen for further studies. The results show that SEELA mediated cis-activated transcription of the nearby oncogene Serine incorporate 2 (SERINC2) by directly binding to the K31 amino acid (aa) of histone H4. Chromatin-bound SEELA strengthens the interaction between chromatin and histone modifiers to promote histone recognition and oncogene transcription. Further studies show that the SEELA-SERINC2 axis regulated aspects of cancer metabolism, such as sphingolipid synthesis, to affect leukemia progression. Conclusions This study shows that lnc-eRNAs are epigenetically activated by cancer-initiating oncoproteins and uncovers a cis-activating mechanism of oncogene transcription control based on lnc-eRNA-mediated epigenetic regulation of enhancer activity, providing insights into the critical roles of lnc-eRNAs in cancer initiation and progression.

scholarly journals A novel cis-acting DNA element required for a high level of inducible expression of the rat P-450c gene.

1990 ◽  
Vol 10 (4) ◽  
pp. 1470-1475 ◽  
Author(s):  
A Yanagida ◽  
K Sogawa ◽  
K I Yasumoto ◽  
Y Fujii-Kuriyama
Keyword(s):  
Regulatory Element ◽  
Consensus Sequence ◽  
Inducible Expression ◽  
Recognition Sequence ◽  
Mobility Shift ◽  
Enhancer Activity ◽  
Cis Acting ◽  
Tata Sequence ◽  
Gel Mobility Shift ◽  
High Level

A novel cis-acting regulatory element (designated BTE for basic transcription element) was found in the region proximal to the TATA sequence of the P-450c gene by the use of deletion mutations. This DNA element is considered to be involved in the basic transcription of the gene and does not show distinct enhancer activity in itself. Together with the XRE sequence (A. Fujisawa-Sehara, K. Sogawa, M. Yamane, and Y. Fujii-Kuriyama, Nucleic Acids Res. 15:4179-4191, 1987), however, this sequence is required for a high inducible expression of the P-450c gene in response to xenobiotic inducers. The BTE sequence contained the GC box consensus sequence and half of the NF-1-binding consensus or CAT box sequence, but their synthetic oligonucleotides, used as competitors in the gel mobility shift assays, did not compete with the BTE sequence for the binding protein, suggesting that the BTE sequence functions as a different recognition sequence from that for Sp1 or NF-1. Analogous sequences to BTE are found in the region proximal to the TATA sequence of other genes, especially other P-450 genes with different modes of regulation, suggesting that the BTE sequence plays a common regulatory role in basic transcription of genes including a group of the P-450 superfamily. The ubiquitous distribution of nuclear factor(s) binding to this element supports this suggestion.

scholarly journals A complex regulatory element from the yeast gene ENO2 modulates GCR1-dependent transcriptional activation.

1993 ◽  
Vol 13 (4) ◽  
pp. 2623-2633 ◽  
Author(s):  
C E Willett ◽  
C M Gelfman ◽  
M J Holland
Keyword(s):  
Binding Site ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Regulatory Element ◽  
Enhancer Element ◽  
Cis Acting ◽  
Genes Encoding ◽  
High Level ◽  
Yeast Genes ◽  
Yeast Enolase

The GCR1 gene product is required for maximal transcription of many yeast genes including genes encoding glycolytic enzymes. Transcription of the yeast enolase gene ENO2 is reduced 50-fold in strains carrying a gcr1 null mutation. cis-acting sequences that are sufficient for GCR1-dependent regulation of ENO2 expression were identified by using an enhancerless CYC1 promoter which is not normally dependent on GCR1 for expression. A 60-bp ENO2 sequence that was sufficient to provide high-level, GCR1-dependent transcriptional activation of the CYC1 promoter was identified. This 60-bp element could be subdivided into a 30-bp sequence containing a novel RAP1-binding site and a GCR1-binding site which did not activate CYC1 transcription and a 30-bp sequence containing a novel enhancer element that conferred moderate levels of GCR1-independent transcriptional activation. The 60-bp CGCR1-dependent upstream activator sequence is located immediately downstream from previously mapped overlapping binding sites for the regulatory proteins ABFI and RAP1. Evidence is presented that the overlapping ABFI- and RAP1-binding sites function together with sequences that bind GCR1 and RAP1 to stage transcriptional activation of ENO2 expression.

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