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Tae-kyung Kim - One of the best experts on this subject based on the ideXlab platform.

  • Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF
    2021
    Co-Authors: Vladyslava Gorbovytska, Seung-kyoon Kim, Filiz Kuybu, Michael Götze, Keunsoo Kang, Andreas Pittroff, Lisa-marie Schneider, Alexander Leitner, Tae-kyung Kim
    Abstract:

    ABSTRACTEnhancer RNAs (eRNAs) are long non-coding RNAs that originate from Enhancers. Although eRNA transcription is a canonical feature of activated Enhancers, the molecular features required for eRNA function and the mechanism of how eRNAs impinge on target gene transcription have not been established. Thus, using eRNA-dependent RNA polymerase II (Pol II) pause release as a model, we examined the requirement of sequence, structure and length of eRNAs for their ability to stimulate Pol II pause release by detaching NELF from paused Pol II. We found eRNA not to exert their function through common structural or sequence motifs. Instead, efficient NELF release requires a single eRNA molecule that must contain unpaired guanosines to make multiple, allosteric contacts with several NELF subunits. By revealing the molecular determinants for eRNA function, our study mechanistically links eRNAs to Pol II pause release and provides new insight into the regulation of metazoan transcription.

  • Enhancer RNAs: a class of long noncoding RNAs synthesized at Enhancers.
    Cold Spring Harbor perspectives in biology, 2015
    Co-Authors: Tae-kyung Kim, Martin Hemberg, Jesse M. Gray
    Abstract:

    Recent studies have revealed that active Enhancers are transcribed, producing a class of noncoding RNAs called Enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription. Emerging studies, showing that eRNAs function in controlling mRNA transcription, challenge the idea that Enhancers are merely sites of transcription factor assembly. Instead, communication between promoters and Enhancers can be bidirectional with promoters required to activate Enhancer transcription. Reciprocally, eRNAs may then facilitate Enhancer-promoter interaction or activate promoter-driven transcription.

  • Enhancer RNA facilitates NELF release from immediate early genes.
    Molecular cell, 2014
    Co-Authors: Katie Schaukowitch, Jae Yeol Joo, Xihui Liu, Jonathan K. Watts, Carlos Martinez, Tae-kyung Kim
    Abstract:

    Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active Enhancers, whose function and action mechanism are yet to be firmly established. Here we show that eRNAs facilitate the transition of paused RNA polymerase II (RNAPII) into productive elongation by acting as a decoy for the negative elongation factor (NELF) complex upon induction of immediate early genes (IEGs) in neurons. eRNAs are synthesized prior to the culmination of target gene transcription and interact with the NELF complex. Knockdown of eRNAs expressed at neuronal Enhancers impairs transient release of NELF from the specific target promoters during transcriptional activation, coinciding with a decrease in target mRNA induction. The Enhancer-promoter interaction was unaffected by eRNA knockdown. Instead, chromatin looping might enable eRNAs to act locally at a specific promoter. Our findings highlight the spatiotemporally regulated action mechanism of eRNAs during early transcriptional elongation.

  • widespread transcription at neuronal activity regulated Enhancers
    Nature, 2010
    Co-Authors: Tae-kyung Kim, Martin Hemberg, Jesse M. Gray, Allen M Costa, Daniel M Bear, David A Harmin, Mike Laptewicz, Kellie Barbarahaley, Scott Kuersten, Eirene Markenscoffpapadimitriou
    Abstract:

    We used genome-wide sequencing methods to study stimulus-dependent Enhancer function in mouse cortical neurons. We identified approximately 12,000 neuronal activity-regulated Enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at Enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of Enhancers. Notably, RNAPII at Enhancers transcribes bi-directionally a novel class of Enhancer RNAs (eRNAs) within Enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal Enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at Enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of Enhancer activation involves RNAPII binding and eRNA synthesis.

Yu Zhao - One of the best experts on this subject based on the ideXlab platform.

  • MyoD induced Enhancer RNA interacts with hnRNPL to activate target gene transcription during myogenic differentiation.
    Nature communications, 2019
    Co-Authors: Yu Zhao, Jiajian Zhou, Jie Yuan, Kun Sun, Xiaona Chen, Xichen Bao, Miguel A. Esteban, Hao Sun
    Abstract:

    Emerging evidence supports roles of Enhancer RNAs (eRNAs) in regulating target gene. Here, we study eRNA regulation and function during skeletal myoblast differentiation. We provide a panoramic view of Enhancer transcription and categorization of eRNAs. Master transcription factor MyoD is crucial in activating eRNA production. Super Enhancer (se) generated seRNA-1 and -2 promote myogenic differentiation in vitro and in vivo. seRNA-1 regulates expression levels of two nearby genes, myoglobin (Mb) and apolipoprotein L6 (Apol6), by binding to heterogeneous nuclear ribonucleoprotein L (hnRNPL). A CAAA tract on seRNA-1 is essential in mediating seRNA-1/hnRNPL binding and function. Disruption of seRNA-1-hnRNPL interaction attenuates Pol II and H3K36me3 deposition at the Mb locus, in coincidence with the reduction of its transcription. Furthermore, analyses of hnRNPL binding transcriptome-wide reveal its association with eRNAs is a general phenomenon in multiple cells. Collectively, we propose that eRNA-hnRNPL interaction represents a mechanism contributing to target mRNA activation.

  • Alterations of androgen receptor-regulated Enhancer RNAs (eRNAs) contribute to enzalutamide resistance in castration-resistant prostate cancer
    Oncotarget, 2016
    Co-Authors: Jingwen Zhao, Yu Zhao, Liguo Wang, Manish Kohli, Jun Zhang, Jeffrey Karnes, Guixia Wang, Haojie Huang
    Abstract:

    Enzalutamide is a second-generation anti-androgen for treatment of castration-resistant prostate cancer (CPRC). It prolongs survival of CRPC patients, but its overall survival benefit is relatively modest (4.8 months) and by 24 months most patients progress on enzalutamide. To date, however, the molecular mechanisms underlying enzalutamide resistance remain elusive. Herein, we report enzalutamide treatment-induced alterations of androgen receptor (AR)-regulated Enhancer RNAs (AR-eRNAs) and their roles in enzalutamide-resistant growth and survival of CRPC cells. AR chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) and RNA-seq analyses revealed that 188 and 227 AR-eRNAs were differentially expressed in enzalutamide-resistant LNCaP and C4-2 cells, respectively. The AR-eRNAs upregulated in C4-2 cells and downregulated in LNCaP cells were selected through meta-analysis. Expression of AR-eRNAs and related mRNAs in the loci of FTO, LUZP2, MARC1 and NCAM2 were further verified by real-time RT-PCR. Silencing of LUZP2 inhibited, but silencing of MARC1 increased the growth of enzalutamide-resistant C4-2 cells. Intriguingly, meta-analysis showed that expression of LUZP2 mRNA increased in primary tumors compared to normal prostate tissues, but decreased again in metastatic CRPC. Our findings suggest that eRNA alteration profiling is a viable new approach to identify functional gene loci that may not only contribute to enzalutamide-resistant growth of CRPC, but also serve as new targets for CRPC therapy.

  • Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer.
    Cell reports, 2016
    Co-Authors: Yu Zhao, Liguo Wang, Shancheng Ren, Lan Wang, Patrick R. Blackburn, Melissa S. Mcnulty, Xu Gao, Meng Qiao, Robert L. Vessella, Manish Kohli
    Abstract:

    The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound Enhancers remain unclear. Here, we identify a group of AR-regulated Enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

Shannon M. Lauberth - One of the best experts on this subject based on the ideXlab platform.

  • Enhancer RNAs are an important regulatory layer of the epigenome.
    Nature structural & molecular biology, 2020
    Co-Authors: Vittorio Sartorelli, Shannon M. Lauberth
    Abstract:

    Noncoding RNAs (ncRNAs) direct a remarkable number of diverse functions in development and disease through their regulation of transcription, RNA processing and translation. Leading the charge in the RNA revolution is a class of ncRNAs that are synthesized at active Enhancers, called Enhancer RNAs (eRNAs). Here, we review recent insights into the biogenesis of eRNAs and the mechanisms underlying their multifaceted functions and consider how these findings could inform future investigations into Enhancer transcription and eRNA function.

  • Enhancer RNAs are an important regulatory layer of the epigenome
    Nature Structural & Molecular Biology, 2020
    Co-Authors: Vittorio Sartorelli, Shannon M. Lauberth
    Abstract:

    Noncoding RNAs (ncRNAs) direct a remarkable number of diverse functions in development and disease through their regulation of transcription, RNA processing and translation. Leading the charge in the RNA revolution is a class of ncRNAs that are synthesized at active Enhancers, called Enhancer RNAs (eRNAs). Here, we review recent insights into the biogenesis of eRNAs and the mechanisms underlying their multifaceted functions and consider how these findings could inform future investigations into Enhancer transcription and eRNA function. Lauberth and Sartorelli consider and discuss recent insights into the biogenesis and function of Enhancer RNAs and the key roles they play in the regulation of gene expression.

  • The role of Enhancer RNAs in epigenetic regulation of gene expression.
    Transcription, 2019
    Co-Authors: Homa Rahnamoun, Paola Orozco, Shannon M. Lauberth
    Abstract:

    Since the discovery that Enhancers can support transcription, the roles of Enhancer RNAs have remained largely elusive. We identified that Enhancer RNAs interact with and augment bromodomain engagement with acetylated chromatin. Here, we discuss our recent findings and the potential mechanisms underlying the regulation and functions of Enhancer RNA-bromodomain associations.

Kelly Maurer - One of the best experts on this subject based on the ideXlab platform.

  • il 1 transcriptional responses to lipopolysaccharides are regulated by a complex of rna binding proteins
    Journal of Immunology, 2020
    Co-Authors: Li Song, Kelly Maurer, Vishesh R Patel, Michelle E Leonard, Kenyaita M Hodge, Annabel Torres, Alessandra Chesi, Sumei Lu, Chun Su, Struan F.a. Grant
    Abstract:

    The IL1A and IL1B genes lie in close proximity on chromosome 2 near the gene for their natural inhibitor, IL1RN Despite diverse functions, they are all three inducible through TLR4 signaling but with distinct kinetics. This study analyzed transcriptional induction kinetics, chromosome looping, and Enhancer RNA production to understand the distinct regulation of these three genes in human cells. IL1A, IL1B, and IL1RN were rapidly induced after stimulation with LPS; however, IL1B mRNA production was less inhibitable by iBET151, suggesting it does not use pause-release regulation. Surprisingly, chromatin looping contacts between IL1A and IL1B were highly intermingled, although those of IL1RN were distinct, and we focused on comparing IL1A and IL1B transcriptional pathways. Our studies demonstrated that Enhancer RNAs were produced from a subset of the regulatory regions, that they were critical for production of the mRNAs, and that they bound a diverse array of RNA binding proteins, including p300 but not CBP. We, furthermore, demonstrated that recruitment of p300 was dependent on MAPKs. Integrator is another RNA binding protein recruited to the promoters and Enhancers, and its recruitment was more dependent on NF-kappaB than MAPKs. We found that integrator and NELF, an RNA polymerase II pausing protein, were associated with RNA in a manner that facilitated interaction. We conclude that IL1A and IL1B share many regulatory contacts, signaling pathways, and interactions with Enhancer RNAs. A complex of protein interactions with Enhancer RNAs emphasize the role of Enhancer RNAs and the overall structural aspects of transcriptional regulation.

  • Enhancer RNA and NFκB-dependent P300 regulation of ADAMDEC1.
    Molecular immunology, 2018
    Co-Authors: Lihua Shi, Kelly Maurer, Zhe Zhang, Michelle Petri, Kathleen E. Sullivan
    Abstract:

    We observed increased expression of ADAMDEC1 RNA in monocytes from patients with systemic lupus erythematosus. The precise role of ADAMDEC1 is uncertain and uniquely among metalloproteinases it utilizes a zinc-coordinating aspartic acid residue which allows it to escape inhibition by tissue inhibitor of metalloprotease-3 (TIMP-3). A closely related gene encodes the protein ADAM28, which is not up-regulated in lupus. We leveraged the ability to look at both gene’s promoters and Enhancers simultaneously. ADAMDEC1 was up-regulated by LPS while ADAM28 was not upregulated in the short term. We identified MAP kinases and NFκB as critical cell pathways regulating the expression of ADAMDEC1. These same pathways were implicated in driving the expression of the ADAMDEC1 upstream Enhancer RNAs. We demonstrated that binding of the Enhancer RNAs produced from the upstream Enhancer were critically important and that p300 bound to both the RNA from the Enhancer and the DNA at the Enhancer. P300 binding to the Enhancer was dependent on NFκB. These data define the critical pathways regulating the expression of ADAMDEC1 and extend our knowledge of the roles of Enhancer RNAs and mechanistically links p300 and Enhancer RNAs.

  • SERPINB2 is regulated by dynamic interactions with pause-release proteins and Enhancer RNAs.
    Molecular immunology, 2017
    Co-Authors: Lihua Shii, Kelly Maurer, Li Song, Zhe Zhang, Kathleen E. Sullivan
    Abstract:

    The SERPINB2 gene is strongly upregulated in inflammatory states. In monocytes, it can constitute up to 1% of total cellular protein. It functions in protection from proteotoxic stress and plays a role in angioedema. The purpose of this study was to define the roles of Enhancer RNAs embedded in the SERPIN gene complex. We found that the upstream Enhancer RNAs upregulated SERPINB2 and the Enhancer RNAs were expressed prior to those of SERPINB2 mRNA. Studies of the SERPINB2 promoter demonstrated the presence of an RNA polymerase II pause-inducing protein, NELF. Stimulation with LPS led to recruitment of the pause-releasing kinase P-TEFb and departure of the pause-inducing protein NELF. RNA immunoprecipitation revealed that NELF and the CDK9 component of P-TEFb bound to the Enhancer RNAs after stimulation with distinct kinetics. Knock-down of the Enhancer RNAs compromised stimulus induction of promoter and Enhancer chromatin changes. Conversely, over-expression was associated with enhanced recruitment of c-JUN and increased expression of SERPINB2 mRNA expression. This study is the first to associate Enhancer RNAs with SERPINB2 and is the first demonstration of acquisition of NELF binding by Enhancer RNAs on chromatin.

Kathleen E. Sullivan - One of the best experts on this subject based on the ideXlab platform.

  • Enhancer RNA and NFκB-dependent P300 regulation of ADAMDEC1.
    Molecular immunology, 2018
    Co-Authors: Lihua Shi, Kelly Maurer, Zhe Zhang, Michelle Petri, Kathleen E. Sullivan
    Abstract:

    We observed increased expression of ADAMDEC1 RNA in monocytes from patients with systemic lupus erythematosus. The precise role of ADAMDEC1 is uncertain and uniquely among metalloproteinases it utilizes a zinc-coordinating aspartic acid residue which allows it to escape inhibition by tissue inhibitor of metalloprotease-3 (TIMP-3). A closely related gene encodes the protein ADAM28, which is not up-regulated in lupus. We leveraged the ability to look at both gene’s promoters and Enhancers simultaneously. ADAMDEC1 was up-regulated by LPS while ADAM28 was not upregulated in the short term. We identified MAP kinases and NFκB as critical cell pathways regulating the expression of ADAMDEC1. These same pathways were implicated in driving the expression of the ADAMDEC1 upstream Enhancer RNAs. We demonstrated that binding of the Enhancer RNAs produced from the upstream Enhancer were critically important and that p300 bound to both the RNA from the Enhancer and the DNA at the Enhancer. P300 binding to the Enhancer was dependent on NFκB. These data define the critical pathways regulating the expression of ADAMDEC1 and extend our knowledge of the roles of Enhancer RNAs and mechanistically links p300 and Enhancer RNAs.

  • SERPINB2 is regulated by dynamic interactions with pause-release proteins and Enhancer RNAs.
    Molecular immunology, 2017
    Co-Authors: Lihua Shii, Kelly Maurer, Li Song, Zhe Zhang, Kathleen E. Sullivan
    Abstract:

    The SERPINB2 gene is strongly upregulated in inflammatory states. In monocytes, it can constitute up to 1% of total cellular protein. It functions in protection from proteotoxic stress and plays a role in angioedema. The purpose of this study was to define the roles of Enhancer RNAs embedded in the SERPIN gene complex. We found that the upstream Enhancer RNAs upregulated SERPINB2 and the Enhancer RNAs were expressed prior to those of SERPINB2 mRNA. Studies of the SERPINB2 promoter demonstrated the presence of an RNA polymerase II pause-inducing protein, NELF. Stimulation with LPS led to recruitment of the pause-releasing kinase P-TEFb and departure of the pause-inducing protein NELF. RNA immunoprecipitation revealed that NELF and the CDK9 component of P-TEFb bound to the Enhancer RNAs after stimulation with distinct kinetics. Knock-down of the Enhancer RNAs compromised stimulus induction of promoter and Enhancer chromatin changes. Conversely, over-expression was associated with enhanced recruitment of c-JUN and increased expression of SERPINB2 mRNA expression. This study is the first to associate Enhancer RNAs with SERPINB2 and is the first demonstration of acquisition of NELF binding by Enhancer RNAs on chromatin.