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Epigenetic regulation by Long Noncoding RNAs

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Lee Jong In

on 4 January 2013

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Transcript of Epigenetic regulation by Long Noncoding RNAs

Jeannie T.Lee Epigenetic Regulation
by Long Noncoding RNAs Content Background Lessons from the X Chromosome Why Long Noncoding RNAs? Local and Genome-Wide Control Prospects and Conclusions Background RNA has become widely suspected as the culprit behind almost every case of epigenetics Once regarded primarily as mere intermediary of the "Central dogma" Only 1% of the mammalian genome
caries protein-coding potential 70 ~ 90% of genome is transcribed at some point during development to produce a large transcriptome of long noncoding RNA "Little Doubt" "Dark Matter" The ENCODE project has revealed an enormous complexity, with ~10 isoforms overlapping any previously annotated genes Pervasive Transcription Occur This universally functional
activity is unknown These transcripts are often poorly conserved, unstable, and/or present in few copies Clear roles have emerged for some lncRNAs,
and a survey of some examples illustrates how this class of RNA is helping to establish new paradigms for epigenetic regulation Lessons from the X Chromosome lncRNas first debuted in the phenomena of genomic imprinting and X-chromosome inactivation X-inactivation center(Xic) The most abundance of lncRNA To balance X-chromosome gene expression between males and females X-chromosome inactivation(XCI) Controls the initiation steps of XCI through a series of RNA-based switches Today, the Xic serves as a model for understading epigenetic regulation by lncRNA X-inactive-specifidc transcript(Xist) One of the first lncRNAs to be discovered in mammals Xist locus produces a 17- ~ 20-kb RNA The RNA coats the X chromosome in cis,
is expressed only from the inactive X chromosome It implied that RNA itself could be an effector
of chromatin and transcriptional change Polycomb repressive complex2(PRC2) and YY1 Through a Repeat A, Xist RNA directly binds PRC2, and targets PRC2 to the Xi lncRNAs may be crucial accessory factors for Polycomb function Polycomb repressive complex2(PRC2) The epigenetic complex responsible for trimethylation of histone H3 at Lys(H3K27me3) http://www.sciencedirect.com/science/article/pii/S0012160612002199 Like other regulatory factors, epigenetic complexes must be targeted in space and time However, many, such as PRC2, do not possess sequence-specific DNA-binding subunits to guide them The involvement of RNA, a marcromolecule with inherent sequence information, would at

once provide targeting specificity and

introduce new regulatory capabilities A region of DNA or RNA that regulates the expression of genes located cis-regulatory trans-regulatory acting from a same molecule acting from a different molecule Xist is controlled by two other lncRNAs Negatively(Tsix) Positively(Jpx) Tsix regulates Xist in several ways It blocks recruitment of PRC2 to Xist by RepA Tsix RNA directly binds PRC2 and also duplexes with Xist-RepA RNA It recruits DNA methyltransferase(Dnmt3a) to silence Xist TsiTsix determines allelic choice by repressing Xist transcription on one allele Tsix coordinates X-chromosome pairing to generate epigenetic asymmetry within the Xist locus Deleting Jpx abolishes Xist activation Its post-transcriptional knockdown recapitulates the deletion Autosomal expression of Jpx rescues the X-linked deletion Jpx is diffusible and acts in trans as an RNA These studies demonstrate central functions for lncRNA during XCI Directly target repressive epigenetic complexes Act as antisense inhibitors activate transcription Why Long Noncodin RNAs? Local and Genome-Wide Control Prospects and Conclusions Evolution of random XCI 150million years ago lncRANs offer distinct advantages over proteins for some forms of epigenetic regulation allelic and cis control were major driving forces Two properties of mammalian lncRNAs are notably relevant Tethering capabilities
and fast turn over Ability to specify a unique address through use of a large sequence space Tethering could be enhanced by a proteins, such as YY1 RNA-DNA-polymerase(Pol2) ternary complex Rapid degradation after transcriptional termination would limit the RNA's half life Preventing diffusion and action at ectopic sites Tsix's half-life of 30 ~ 60 min degraded as soon as it is created(40-kb) Explaining its strict cis action lncRNAs are distinguished from proteins and small RNAs by possibility of allele-specific action Transcription factors necessarily act within large networks and affect hundreds of genes at once lncRNAs enables delivery of epigenetic complexes to a unique address Transcription factors recognize short DNA motifs lncRNAs like Tsix and RepA/Xist occur only once site-specific
lncRNAs Network-based transcription factors Chromatin modifiers Spatial and Temporal specificity
during development Collaboration Example Oct4 Leukemia inhibitory factor Bone morphogenetic protein signaling in pluripotent cells activate a genome-wide transcription program Genome-wide control Local Control Tsix and Xite Oct4 in Xic activate Breaking the symmetry between the future Xa and Xi The thousands of transcription factors and lncRNAs operating in parallel local and genome-wide changes
for development and for discrete responses to environmental signals Classes of lncRNAs Genomic imprinting Genes are expressed from the allele of only one parent Activators Pseudogenes as regulators Serve as activators of gene expression Beyond allelic phenomena LncRNA's function is not limited to the control of allelic expression Fundamental Differences: Cis vs Trans H19 One of the first lncRNAs to be identified Reciprocally imprinted with insulin-like growth factor(Igf2) and highly expressed However its deletion has no phenotype Now apears to function as microRNA In the PRC2 transcriptome RIP-seq(RNA immunoprecipitation) analysis identify thousands of RNAs PRC2 and the LSD1/REST/coREST complex associate with hundreds of RNA That promoters of Polycomb target genes often make short transcripts that also associate with PRC2 Noncoding RNAs frequently localize to gene promoters These promoter-associated short RNAs(PASRs) are typically short and have been considered abortive transcrip made by stalled or paused polymerases Pausing or stalling could prolong tethering and facilitate recruitment of factors LncRNAs also originate within retrotransposons, the ubiquitous repetitive elements once regarded as junk In XCI Jpx RNA is required to induce Xist expression Principles governing repressive lncRNA could also apply to activating lncRNAs But much work remains to be done in this area because mechanistic details are currently lacking Pseudogenes are characterized by a combination of homology to a known gene and nonfunctionality Pseudogene space may turn out to be a vast repository of regulatory lncRNAs A region of DNA or RNA that regulates the expression of genes located cis-regulatory trans-regulatory acting from a same molecule acting from a different molecule The lncRNA field has now grown to include mainstream biochemists, genomicists, and computational biologists Related issues are the inherent differences in comparing knockout to knockdown phenotypes Analysis of lncRNA function would ideally also include gain-of-function experiments and to distinguish among RNA, transcriptional activity, and underlysing chromatin as the mechanism of action for a noncoding locus LncRNAs are now kown to confer a degree of temporal and spatial specificity not possible with proteins and small RNAs Allelic and locus specific control might have been a major driving force behind the genome-wide fixation of lncRNAs With the site-specific action of cis-acting lncRNAs, drugs designed against lncRNAs could circumvent pleiotropic effects that plague many current treatment modalities that target enzymatic activities within epigenetic complexes Classes of lncRNA Fundamental differences:Cis vs Trans
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