In eukaryotic cells, transcription begins with rna polymerase binding to the promoters. Almost a decade ago, the discovery of their pervasive transcription into noncoding rnas, termed enhancer rnas ernas, opened a whole new field of study. Here, we focus on the mechanisms that control t cell differentiation, with a particular focus on the role of regulatory elements encoded within the genome, known as transcriptional enhancers. Transcriptional landscape and clinical utility of enhancer rnas for ernatargeted therapy in cancer. Dna methylation is widely involved in transcriptional repression in mammals, with dna methyltransferases dnmts methylating cytosines m 5 c in cpgrich sequences. Enhancers are cisregulatory elements in the genome that cooperate with promoters to control target gene transcription. Genomewide mapping and characterization of notch regulated long noncoding rnas in acute leukemia. Such precise control is crucial for the switching of the transcriptional program. Growing evidence has demonstrated that all three major dnmts dnmt1, dnmt3a, and dnmt3b in mammals bind to and can be regulated by noncoding rnas. Enhancer rnas may also act as epigenetic regulators that maintain an active chromatin state at transcribed gene loci.
A hypermethylation strategy utilized by enhancerbound. Myod induced enhancer rna interacts with hnrnpl to. Diversity and emerging roles of enhancer rna in regulation. In addition to ernas, a plethora of lncrnas are already reported to play activating roles in gene transcription regulation 35, 43. Franco the lineberger comprehensive cancer center, department of genetics, university of north. Genomewide analysis and functional prediction of the. Glassenhancer rnas and regulated transcriptional programs. Enhancer rnas and regulated transcriptional programs michael t. Tal1scl is a prime example of an oncogenic transcription factor that is abnormally expressed in acute leukemia due to the replacement of regulator elements. Tbx4 is involved in the super enhancer driven transcriptional programs underlying features specific to lung fibroblasts. Flowchart representing key steps for the computational identification of eotrs and the analysis of ti transcriptional interference acting on human enhancer domains in hepg2 and hela cell lines a. Inflammationsensitive super enhancers form domains of coordinately regulated enhancer rnas.
Despite recent advances in direct cell lineage reprogramming, little is known about the transcriptional regulatory networks underlying the cellular identity of fibroblasts derived from various organs. Mechanism of other ncrnas that positively regulate gene expression. The regulation mechanism and functional role of sernas are still unclear. Long noncoding rnas lncrnas are a subclass within noncoding rna repertoire that have emerged as crucial regulators of the gene expression in various pathophysiological conditions. Here, we report that a biochemical complex containing a potential chromatin reader, rack7, and the histone lysine 4 trimethyl h3k4me3specific demethylase kdm5c occupies many active enhancers, including almost all superenhancers. Enhancer rnas participate in androgen receptordriven looping. Genomewide analysis of oct4 targeting of this program suggests a novel role of oct4mediated transcriptional regulation of lncrnas. The oncogenic transcription factor tal1 regulates the transcriptional program in tall.
Suppression of enhancer overactivation by a rack7histone. We have witnessed an exceptional expansion of super enhancer research in oncology and beyond. Functional roles of enhancer rnas for oestrogendependent. Furthermore, our data show that klk3 erna klk3e selectively enhances the gene expression of ar regulated genes, and provide. Current advances on the important roles of enhancer rnas. Regulation of enhancer activity is important for controlling gene expression programs. In the current study, we have shown that oct4 transcriptionally activated oncogenic lncrnas expression through promoter or enhancer binding regulation. Adipogenesis is a fundamental aspect of adipose tissue biology. Oncogenic transcriptional program driven by tal1 in tcell. Transcription start site profiling uncovers divergent. Enhancer rnas participate in androgen receptordriven. Transcriptional landscape of the human cell cycle pnas.
Noncoding rnas regulating the transcriptional machinery. Long noncoding rnas lncrnas have emerged as additional regulators of gene transcription. Regulation of gene expression by enhancer rnas ernas. Collectively, these findings suggest that both enhancer transcription and the resultant enhancer rnas can contribute to enhancer function. Enhancer e2 was selected because the tp63 binding site was located in e2a, and a tp63 motif was observed in this constituent figure 2 b. Accumulating body of evidence based on multitude studies has highlighted the role of. Npas4 regulates a transcriptional program in ca3 required. Figure 3 molecular characteristics of proteincoding rnas, long noncoding rnas lncrnas, and enhancer rnas. Superenhancer function and its application in cancer targeted.
The assembly of the transcriptional apparatus atan enhancer isfirst. Previous studies have reported that ernas are a subclass of long noncoding rnas lncrnas, which play a critical role in gene regulation and. Sep 12, 2019 the e2 regulated mrna and lncrna expression profiles in the mouse uterus indicate an association between lncrnas and mrnas that regulate e2driven pathways and reproductive phenotypes in the mouse. Small rnamediated transcriptional silencing is required for many biological processes, including repression of transposable elements. Cellfate transitions are ultimately driven by changes in gene expression. Enhancer rnas mediate estrogeninduced decommissioning of. Enhancer domains represent complex arrays of tfbss and participate in the formation of preinitiation complexes for rna polymerase ii transcription. Enhancers are genomic elements that have been implicated in the regulation of gene transcription for many years. Peng bl, li wj, ding jc, he yh, ran t, xie bl, wang zr, shen hf, xiao rq, gao ww, ye ty, gao x, liu w. Transcriptional control by enhancers and enhancer rnas. Dec 30, 2019 super enhancer rnas sernas are a kind of noncoding rna transcribed from super enhancer regions.
Targeting oncogenic super enhancers in myc dependent aml. Enhancer rnas ernas represent a class of relatively short noncoding rna molecules 502000 nucleotides transcribed from the dna sequence of enhancer regions. Super enhancer rnas sernas are a kind of noncoding rna transcribed from super enhancer regions. We use this system to couple multiple synthetic and endogenous target genes with specific inducers, and assemble gene regulatory modules demonstrating parallel and orthogonal transcriptional programs. By recruiting rna polymerase ii to promoters and enhancers of target genes, npas4 regulates a learningspecific transcriptional program in ca3 that includes many wellknown activity regulated genes, which suggests that npas4 is a master regulator of activity regulated gene programs and is central to memory formation. Superenhancer rnas sernas are a kind of noncoding rna transcribed. Enhancerderived rnas ernas are a group of rnas transcribed by rna. To investigate the role of tp63 in the transcriptional regulation of linc01503, enhancer e2 was further divided into 2 constituents e2a and e2b for luciferase assay. Abundant studies have indicated that lncrnas are involved in the differentiation, proliferation, activation, and initiation of apoptosis in. Read functional roles of enhancer rnas for oestrogendependent transcriptional activation, nature on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
Indepth analysis of global rna sequencing has enabled a comprehensive overview of cellular transcriptomes and revealed the pervasive transcription of divergent rnas from promoter regions across eukaryotic genomes. Roles of enhancers in development, signaling events, and diseases. Pdf transcriptional control by enhancers and enhancer rnas. Genomewide identification of novel intergenic enhancer. Long noncoding rnas in the regulation of myeloid cells. Bmal1 regulates the expression of clock controlled genes by facilitating the binding of other tfs. In recent years, enhancers have been reported to be widely transcribed, resulting in the generation of enhancer rnas ernas. Thus, for a long time, the question as to how enhancers act in a.
Pdf enhancer rnas and regulated transcriptional programs. Current advances on the important roles of enhancer rnas in. We report that enhancer rnas ernas, a class of long noncoding rnas, participate in the androgen receptor ardependent looping complex that enhances spatial communication of distal enhancers and target promoters, leading to transcriptional activation events. Schematic diagrams of chromatin immunoprecipitation coupled with highthroughput sequencing chipseq or rnaseq analysis centered on the transcription start sites tss to depict the differences and similarities between these four. The transcriptional programs of differentiated cells are tightly regulated by interactions between cell typespecific transcription factors and cisregulatory elements. The enhancer rna ariel activates the oncogenic transcriptional program in tcell acute lymphoblastic leukemia. Long noncoding rnas lncrnas have been attracting immense research interests. Enhancer occlusion transcripts regulate the activity of.
Cell typespecific transcriptional regulation by the clock localizes to rhythmic enhancers that are unique to the. Tbx4 is involved in the superenhancerdriven transcriptional. Inflammationsensitive super enhancers form domains of. Both activation and repression of gene expression are associated with ses and erna.
Recent studies have linked ses in the formation of llps condensates resulting in the convergence of ses, llps, transcriptional regulation and. They were first detected in 2010 through the use of genomewide techniques such as rnaseq and chipseq. The transient e2 regulated transcriptome is reflected in the timedependent shifting of biological processes regulated in the uterus in response to e2. In addition, our analysis identified thousands of enhancer rnas and related transcription factors that are highly correlated with cellcycleregulated transcription but not with steadystate expression, thus highlighting the importance of transcriptional and epigenetic dynamics during cellcycle progression. A major surprise arising from genomewide analyses has been the observation that the majority of the genome is transcribed, generating noncoding rnas ncrnas. Using global nuclear runon sequencing groseq, we find extensive regulation of enhancer rnas ernas within ses in response to lipopolysaccharide lps treatment in macrophages. Markers of transcriptional regulation including rna polymerase ii pol ii sites, transcription factor binding sites, cisregulatory rna structures, histone deacetylase, and histone enhancer hallmarks are common in the dna corresponding to the 3700 rnas detectable only.
Sep 29, 2016 long noncoding rnas lncrnas have been attracting immense research interests. Pdf since the discovery that enhancers can support transcription, the roles of enhancer rnas have remained largely elusive. Highdepth tss mapping is a powerful strategy for identifying and characterizing lowabundance andor lowstability rnas. Furthermore, our data show that klk3 erna klk3e selectively enhances the gene expression of ar regulated genes, and provide evidence. Long noncoding rnas lncrnas have been proven to play important roles in transcriptional processes and biological functions. Small rnas loaded into argonaute family proteins direct repressive histone modifications or dna cytosine methylation to homologous regions of the genome. More recently, enhancers have been found to be broadly transcribed, resulting in the production of enhancer. Potentially, rna polymerase template switching between promoter and enhancer could cause spurious transcriptional initiation and, in turn, lead to the generation of these enhancer derived rnas. Revealing the gene regulation networks governing cancer initiation and development is necessary while it remains uncompleted. Enhancer rnas and regulated transcriptional programs. These studies disclosed that genomes encode a vast repertoire of rnas beyond the wellknown proteincoding messenger rnas. Furthermore, treatment with cortistatin a ca, which inhibits mediator kinases including cdk8, increased the expression of tumor suppressor genes regulated by super enhancers and inhibited aml progression in a xenograft model, suggesting that mediatorassociated kinases can act as negative regulators of genes regulated by super enhancers. Enhancers contain specific recognition sequences required for binding of transcription factors tf that regulate gene expression in a spatial and.
We therefore developed a comprehensive database for human transcriptional regulation of lncrnas. Oct4 transcriptionally regulates the expression of long. A hypermethylation strategy utilized by enhancer bound carm1 to promote estrogen receptor. Li w, notani d, ma q, tanasa b, nunez e, chen ay, merkurjev d, zhang j, ohgi k, song x, oh s, et al. Superenhancer function and its application in cancer. Current evidence indicates that lncrnas are a very heterogeneous group of molecules. Although accumulating evidence has demonstrated that individual enhancer rnas ernas exert critical biological functions rather than being passive transcriptio.
They function by promoting transcriptional activity of promoter regions, generally from significant distances away, and in many cases they are the primary transcription factor binding site. Enhancer occlusion transcripts regulate the activity of human. Noncoding rnas in transcriptional regulation springerlink. Meanwhile, active enhancers and superenhancers also produce transcripts termed enhancer rnas ernas from their dna elements. Pdf the enhancer rna ariel activates the oncogenic. Although superenhancers play a critical role in the core transcriptional regulatory circuity of embryonic stem cell esc differentiation, whether sernas have similar properties should be further investigated. Surprisingly, majority 90% of the differentially regulated plncrnas were induced upon hypoxia stimulus, in contrast to ernas that showed an approximately equal distribution of expression change directions figure 2a. Enhancers endow the brain with its incredible diversity of cell types and also translate neural activity into gene induction. Collectively, these findings suggest that both enhancer transcription and the resultant enhancer rnas can contribute to enhancer.
Pdf the role of enhancer rnas in epigenetic regulation. The authors show that depletion of ernas expressed from estrogenbinding sites diminishes the activation of the target genes. N2 in the past few years, technological advances in nucleotide sequencing have culminated in a greater understanding of the complexity of the human transcriptome. The core transcriptional circuitry that governs preadipocyte commitment and adipocyte differentiation has been elucidated in the last two decades along with the cellular origins of adipocyte progenitors 1,65. This gene has also been recognized as an essential regulator of hematopoiesis. Chromatinenriched rnas mark active and repressive cis. Superenhancers ses in a broad range of human cell types are large clusters of enhancers with aberrant high levels of transcription factor binding, which are central to drive expression of genes in controlling cell identity and stimulating oncogenic transcription. Frontiers long noncoding rnas as local regulators of. Enhancer rnas may play a role in stabilising the binding of transcription factors to enhancers, positively reinforcing the association. In addition to widespread transcription of long noncoding rnas lncrnas in mammalian cells, bidirectional ncrnas are transcribed on enhancers, and are thus referred to as enhancer rnas ernas. Function and mechanism of long noncoding rnas in adipocyte.
Enhancers are cisacting elements that have the ability to increase the expression of target genes. Emerging evidence supports roles of enhancer rnas ernas in regulating target gene. Frontiers transcriptional profiling of hypoxiaregulated. Frontiers transcriptional enhancers in the regulation of. These studies have increased our understanding of the hierarchy and dynamics of chromatin domains that facilitate cognate enhancer promoter looping, defining the transcriptional program of different cell types. A better understanding of the molecular mechanisms of ernas by which they function in the normal and tumor cell will make better understanding of tumor pathogenesis. Ses consist of large clusters of enhancer elements that are formed by the binding of key transcription factors and the mediator coactivator complex. Super enhancers ses are enhancer dense regions found near genes that play key roles in determining cellular identity.
Sprinkled throughout the genome are a million regulatory sequences called transcriptional enhancers that activate gene promoters in the right cells, at the right time. Jun 02, 20 read functional roles of enhancer rnas for oestrogendependent transcriptional activation, nature on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Cancer cells acquire superenhancers at oncogene and cancerous phenotype relies on these abnormal transcription propelled by ses. May 20, 2014 we report that enhancer rnas ernas, a class of long noncoding rnas, participate in the androgen receptor ardependent looping complex that enhances spatial communication of distal enhancers and target promoters, leading to transcriptional activation events. Michael rosenfelds profile, publications, research topics, and coauthors. The relevance of lncrnas in biological and physiological as well as in pathological processes has increased along with the understanding of their various regulatory mechanisms.
Thanks to rapid advances in genomic technologies, it is now possible to identify thousands of. Runx1mediated hematopoietic stemcell emergence is controlled by a gataetsscl regulated enhancer. Functional roles of enhancer rnas for oestrogendependent transcriptional activation. It is now apparent that super enhancers play critical roles in transcriptional regulation, which have the oncogenic capacity or oncosupressive potential in a contextdependent manner.
Jan 04, 2018 it was recently proposed that altering the environmental conditions can reprogram circadian transcriptional programs e. Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell typespecific gene expression programs. Li et al focused on a number of specific ernas produced from enhancers of oestrogen. Transcriptional gene silencing guided by small rnas is a process conserved from protozoa to mammals. Tal1induced regulatory program through the regulation of arid5b. Here, we study erna regulation and function during skeletal. Tal1 expression is strictly regulated in a lineage and stagespecific manner. Enhancer rna discovery and transcriptional properties. Enhancer rnas and regulated transcriptional programs ncbi. Dissecting the transcriptional regulatory networks of. A few master transcription factors govern cell typespecific transcriptional programs by activating tissuespecific superenhancers 42, 50. Enhancers play a central role in the transcriptional regulation of metazoans.
Recent studies have shown that enhancers can act as transcriptional units for the production of enhancer rnas ernas, which are hallmarks of activity enhancers and are involved in the regulation of gene transcription. Unlike promoters, enhancers are not necessarily adjacent to target genes and can exert their functions regardless of enhancer orientations, positions and spatial segregations from target genes. Genomewide identification of novel intergenic enhancer like. Gene expression is regulated by the binding of transcription factors tfs to specific and conserved dna motifs within enhancers and promoters, which then, in collaboration with chromatinmodifying enzymes, leads to target gene activation or repression long et al. Dec 26, 2018 enhancers and superenhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene transcription. Transcriptional control by enhancers and enhancer rnas michael w. Altogether, we were able to define 707 promoterassociated lncrnas plncrna and 1056 enhancer rnas ernas figure 2a. Rnabinding proteins transcriptional and post transcriptional regulation of rna has a role in regulating the patterns of gene expression during development. Transcriptional landscape and clinical utility of enhancer. Regulation of circadian clock transcriptional output by clock. Although enhancers have been identified for more than 30 years, widespread transcription from enhancers are just discovered by. Epigenetic control of transcriptional regulation in. Although super enhancers play a critical role in the core transcriptional regulatory circuity of embryonic stem cell esc differentiation, whether sernas have similar properties should be further investigated. Abstract the functional importance of gene enhancers in regulated gene expression is well established.