Showing papers on "Transcription (biology) published in 2016"

Role of TET enzymes in DNA methylation, development, and cancer

Abstract: The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. The ten eleven translocation (TET) enzymes oxidize 5-methylcytosines (5mCs) and promote locus-specific reversal of DNA methylation. TET genes, and especially TET2, are frequently mutated in various cancers, but how the TET proteins contribute to prevent the onset and maintenance of these malignancies is largely unknown. Here, we highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. In addition, we discuss some of the key outstanding questions in the field.

Genome Regulation by Long Noncoding RNAs

Abstract: The discovery of extensive transcription of long noncoding RNAs (lncRNAs) provide an important new perspective on the centrality of RNA in gene regulation I will discuss genome-scale strategies to

Transcription factors as readers and effectors of DNA methylation

Abstract: Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease.

Transcription upregulation via force-induced direct stretching of chromatin.

Abstract: Local surface forces of physiological magnitudes can directly stretch chromatin and induce transcription upregulation in a living cell.

TT-seq maps the human transient transcriptome

Abstract: Pervasive transcription of the genome produces both stable and transient RNAs. We developed transient transcriptome sequencing (TT-seq), a protocol that uniformly maps the entire range of RNA-producing units and estimates rates of RNA synthesis and degradation. Application of TT-seq to human K562 cells recovers stable messenger RNAs and long intergenic noncoding RNAs and additionally maps transient enhancer, antisense, and promoter-associated RNAs. TT-seq analysis shows that enhancer RNAs are short-lived and lack U1 motifs and secondary structure. TT-seq also maps transient RNA downstream of polyadenylation sites and uncovers sites of transcription termination; we found, on average, four transcription termination sites, distributed in a window with a median width of ~3300 base pairs. Termination sites coincide with a DNA motif associated with pausing of RNA polymerase before its release from the genome.

Base-pair-resolution genome-wide mapping of active RNA polymerases using precision nuclear run-on (PRO-seq)

Abstract: We provide a protocol for precision nuclear run-on sequencing (PRO-seq) and its variant, PRO-cap, which map the location of active RNA polymerases (PRO-seq) or transcription start sites (TSSs) (PRO-cap) genome-wide at high resolution. The density of RNA polymerases at a particular genomic locus directly reflects the level of nascent transcription at that region. Nuclei are isolated from cells and, under nuclear run-on conditions, transcriptionally engaged RNA polymerases incorporate one or, at most, a few biotin-labeled nucleotide triphosphates (biotin-NTPs) into the 3' end of nascent RNA. The biotin-labeled nascent RNA is used to prepare sequencing libraries, which are sequenced from the 3' end to provide high-resolution positional information for the RNA polymerases. PRO-seq provides much higher sensitivity than ChIP-seq, and it generates a much larger fraction of usable sequence reads than ChIP-seq or NET-seq (native elongating transcript sequencing). Similarly to NET-seq, PRO-seq maps the RNA polymerase at up to base-pair resolution with strand specificity, but unlike NET-seq it does not require immunoprecipitation. With the protocol provided here, PRO-seq (or PRO-cap) libraries for high-throughput sequencing can be generated in 4-5 working days. The method has been applied to human, mouse, Drosophila melanogaster and Caenorhabditis elegans cells and, with slight modifications, to yeast.

Transcription factor trapping by rna in gene regulatory elements

Abstract: Disclosed herein are methods useful for modulating expression of a target gene by modulating binding between a ribonucleic acid (RNA) transcribed from at least one regulatory element of a target gene and a transcription factor which binds to both the RNA and the regulatory element. Also disclosed herein are methods and assays for identifying agents that interfere with binding between RNA transcribed from at least one regulatory element and a transcription factor which binds to the RNA and to the regulatory element.

Codon influence on protein expression in E. coli correlates with mRNA levels

Abstract: Degeneracy in the genetic code, which enables a single protein to be encoded by a multitude of synonymous gene sequences, has an important role in regulating protein expression, but substantial uncertainty exists concerning the details of this phenomenon. Here we analyse the sequence features influencing protein expression levels in 6,348 experiments using bacteriophage T7 polymerase to synthesize messenger RNA in Escherichia coli. Logistic regression yields a new codon-influence metric that correlates only weakly with genomic codon-usage frequency, but strongly with global physiological protein concentrations and also mRNA concentrations and lifetimes in vivo. Overall, the codon content influences protein expression more strongly than mRNA-folding parameters, although the latter dominate in the initial ~16 codons. Genes redesigned based on our analyses are transcribed with unaltered efficiency but translated with higher efficiency in vitro. The less efficiently translated native sequences show greatly reduced mRNA levels in vivo. Our results suggest that codon content modulates a kinetic competition between protein elongation and mRNA degradation that is a central feature of the physiology and also possibly the regulation of translation in E. coli.

Transcriptional termination in mammals: Stopping the RNA polymerase II juggernaut

Abstract: Terminating transcription is a highly intricate process for mammalian protein-coding genes. First, the chromatin template slows down transcription at the gene end. Then, the transcript is cleaved at the poly(A) signal to release the messenger RNA. The remaining transcript is selectively unraveled and degraded. This induces critical conformational changes in the heart of the enzyme that trigger termination. Termination can also occur at variable positions along the gene and so prevent aberrant transcript formation or intentionally make different transcripts. These may form multiple messenger RNAs with altered regulatory properties or encode different proteins. Finally, termination can be perturbed to achieve particular cellular needs or blocked in cancer or virally infected cells. In such cases, failure to terminate transcription can spell disaster for the cell.

Influenza virus RNA polymerase: insights into the mechanisms of viral RNA synthesis.

Abstract: The genomes of influenza viruses consist of multiple segments of single-stranded negative-sense RNA. Each of these segments is bound by the heterotrimeric viral RNA-dependent RNA polymerase and multiple copies of nucleoprotein, which form viral ribonucleoprotein (vRNP) complexes. It is in the context of these vRNPs that the viral RNA polymerase carries out transcription of viral genes and replication of the viral RNA genome. In this Review, we discuss our current knowledge of the structure of the influenza virus RNA polymerase, and insights that have been gained into the molecular mechanisms of viral transcription and replication, and their regulation by viral and host factors. Furthermore, we discuss how advances in our understanding of the structure and function of polymerases could help in identifying new antiviral targets.

A CRISPR-based approach for targeted DNA demethylation.

Abstract: In mammalian cells, DNA methylation critically regulates gene expression and thus has pivotal roles in myriad of physiological and pathological processes. Here we report a novel method for targeted DNA demethylation using the widely used clustered regularly interspaced short palindromic repeat (CRISPR)-Cas system. Initially, modified single guide RNAs (sgRNAs) (sgRNA2.0) were constructed by inserting two copies of bacteriophage MS2 RNA elements into the conventional sgRNAs, which would facilitate the tethering of the Tet1 catalytic domain (Tet-CD), in fusion with dCas9 or MS2 coat proteins, to the targeted gene loci. Subsequently, such system was shown to significantly upregulate transcription of the target genes, including RANKL, MAGEB2 or MMP2, which was in close correlation to DNA demethylation of their neighboring CpGs in the promoters. In addition, the dCas9/sgRNA2.0-directed demethylation system appeared to afford efficient demethylation of the target genes with tenuous off-target effects. Applications of this system would not only help us understand mechanistically how DNA methylation might regulate gene expression in specific contexts, but also enable control of gene expression and functionality with potential clinical benefits.

Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development

Abstract: Transcription of a long non-coding RNA, known as upperhand (Uph) located upstream of the HAND2 transcription factor is required to maintain transcription of the Hand2 gene by RNA polymerase, and blockade of Uph expression leads to heart defects and embryonic lethality in mice The expression of the transcription factor HAND2 is controlled by several upstream enhancer elements, confined in a region delimited by the presence of the chromatin mark H3K27Ac Eric Olson and colleagues have found that the transcription of long non-coding RNA located upstream of HAND2 is required to maintained these chromatin marks and let the RNA polymerase transcribe the Hand2 gene Preventing the expression of this long non-coding RNA with a termination cassette leads to defects in heart development in mice HAND2 is an ancestral regulator of heart development and one of four transcription factors that control the reprogramming of fibroblasts into cardiomyocytes1,2,3,4 Deletion of Hand2 in mice results in right ventricle hypoplasia and embryonic lethality1,5 Hand2 expression is tightly regulated by upstream enhancers6,7 that reside within a super-enhancer delineated by histone H3 acetyl Lys27 (H3K27ac) modifications8 Here we show that transcription of a Hand2-associated long non-coding RNA, which we named upperhand (Uph), is required to maintain the super-enhancer signature and elongation of RNA polymerase II through the Hand2 enhancer locus Blockade of Uph transcription, but not knockdown of the mature transcript, abolished Hand2 expression, causing right ventricular hypoplasia and embryonic lethality in mice Given the substantial number of uncharacterized promoter-associated long non-coding RNAs encoded by the mammalian genome9, the Uph–Hand2 regulatory partnership offers a mechanism by which divergent non-coding transcription can establish a permissive chromatin environment

Transcription–replication conflicts: how they occur and how they are resolved

Abstract: The frequent occurrence of transcription and DNA replication in cells results in many encounters, and thus conflicts, between the transcription and replication machineries. These conflicts constitute a major intrinsic source of genome instability, which is a hallmark of cancer cells. How the replication machinery progresses along a DNA molecule occupied by an RNA polymerase is an old question. Here we review recent data on the biological relevance of transcription-replication conflicts, and the factors and mechanisms that are involved in either preventing or resolving them, mainly in eukaryotes. On the basis of these data, we provide our current view of how transcription can generate obstacles to replication, including torsional stress and non-B DNA structures, and of the different cellular processes that have evolved to solve them.

Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins

Abstract: The multiple roles played by RNA binding proteins in neurodegeneration have become apparent following the discovery of TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) involvement in amyotrophic lateral sclerosis and frontotemporal lobar dementia. In these two diseases, the majority of patients display the presence of aggregated forms of one of these proteins in their brains. The study of their functional properties currently represents a very promising target for developing the effective therapeutic options that are still lacking. This aim, however, must be preceded by an accurate evaluation of TDP-43 and FUS/TLS biological functions, both in physiological and disease conditions. Recent findings have uncovered several aspects of RNA metabolism that can be affected by misregulation of these two proteins. Progress has also been made in starting to understand how the aggregation of these proteins occurs and spreads from cell to cell. The aim of this review will be to provide a general overview of TDP-43 and FUS/TLS proteins and to highlight their physiological functions. At present, the emerging picture is that TDP-43 and FUS/TLS control several aspects of an mRNA's life, but they can also participate in DNA repair processes and in non-coding RNA metabolism. Although their regulatory activities are similar, they regulate mainly distinct RNA targets and show different pathogenetic mechanisms in amyotrophic lateral sclerosis/frontotemporal lobar dementia diseases. The identification of key events in these processes represents today the best chance of finding targetable options for therapeutic approaches that might actually make a difference at the clinical level. The two major RNA Binding Proteins involved in Amyotrophic Lateral Sclerosisi and Frontotemporal Dementia are TDP-43 and FUST/TLS. Both proteins are involved in regulating all aspects of RNA and RNA life cycle within neurons, from transcription, processing, and transport/stability to the formation of cytoplasmic and nuclear stress granules. For this reason, the aberrant aggregation of these factors during disease can impair multiple RNA metabolic pathways and eventually lead to neuronal death/inactivation. The purpose of this review is to provide an up-to-date perspective on what we know about this issue at the molecular level. This article is part of the Frontotemporal Dementia special issue.

Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses

Abstract: A common approach to understanding neurodegenerative disease is comparing gene expression in diseased versus healthy tissues. We illustrate that expression profiles derived from whole tissue RNA highly reflect the degenerating tissues' altered cellular composition, not necessarily transcriptional regulation. To accurately understand transcriptional changes that accompany neuropathology, we acutely purify neurons, astrocytes and microglia from single adult mouse brains and analyse their transcriptomes by RNA sequencing. Using peripheral endotoxemia to establish the method, we reveal highly specific transcriptional responses and altered RNA processing in each cell type, with Tnfr1 required for the astrocytic response. Extending the method to an Alzheimer's disease model, we confirm that transcriptomic changes observed in whole tissue are driven primarily by cell type composition, not transcriptional regulation, and identify hundreds of cell type-specific changes undetected in whole tissue RNA. Applying similar methods to additional models and patient tissues will transform our understanding of aberrant gene expression in neurological disease.

Mechanisms of Bacterial Transcription Termination: All Good Things Must End

Abstract: Transcript termination is essential for accurate gene expression and the removal of RNA polymerase (RNAP) at the ends of transcription units. In bacteria, two mechanisms are responsible for proper transcript termination: intrinsic termination and Rho-dependent termination. Intrinsic termination is mediated by signals directly encoded within the DNA template and nascent RNA, whereas Rho-dependent termination relies upon the adenosine triphosphate-dependent RNA translocase Rho, which binds nascent RNA and dissociates the elongation complex. Although significant progress has been made in understanding these pathways, fundamental details remain undetermined. Among those that remain unresolved are the existence of an inactivated intermediate in the intrinsic termination pathway, the role of Rho–RNAP interactions in Rho-dependent termination, and the mechanisms by which accessory factors and nucleoid-associated proteins affect termination. We describe current knowledge, discuss key outstanding questions, and hi...

A single-molecule view of transcription reveals convoys of RNA polymerases and multi-scale bursting

Abstract: Live-cell imaging has revealed unexpected features of gene expression. Here using improved single-molecule RNA microscopy, we show that synthesis of HIV-1 RNA is achieved by groups of closely spaced polymerases, termed convoys, as opposed to single isolated enzymes. Convoys arise by a Mediator-dependent reinitiation mechanism, which generates a transient but rapid succession of polymerases initiating and escaping the promoter. During elongation, polymerases are spaced by few hundred nucleotides, and physical modelling suggests that DNA torsional stress may maintain polymerase spacing. We additionally observe that the HIV-1 promoter displays stochastic fluctuations on two time scales, which we refer to as multi-scale bursting. Each time scale is regulated independently: Mediator controls minute-scale fluctuation (convoys), while TBP-TATA-box interaction controls sub-hour fluctuations (long permissive/non-permissive periods). A cellular promoter also produces polymerase convoys and displays multi-scale bursting. We propose that slow, TBP-dependent fluctuations are important for phenotypic variability of single cells.

Transcriptional Control by the SMADs

Abstract: The transforming growth factor-β (TGF-β) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-β family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

Human HSP70 promoter contains at least two distinct regulatory domains (heat shock induction/cadmium induction/serum stimulation/DNA-mediated gene transfer)

Abstract: The expression of the human HSP70 gene is induced by a wide range of physiological stresses, including exposure to heat shock and heavy metals, or under nonstress conditions, such as in response to serum stimulation. We have previously demonstrated that in either case the regulated expression is at the primary level of transcription. To deter- mine whether transcription is mediated through a single or multiple genetic elements, we have dissected the sequences upstream of the transcription start site of the human HSP70 gene by constructing chimeric genes retaining variable amounts of 5' flanking regions fused to the bacterial gene encoding chloramphenicol acetyltransferase. Transcription from the chimeric genes was determined by SI nuclease analysis of separate stable transfectants. The sequences re- quired for heat shock and cadmium induction lie between -107 and -68. Within this region is the sequence CTGGAATAT- TCCCG, which Is identical in 12/14 positions with the heat shock element of Drosophila heat shock genes, and a separate sequence, CGNCCCGG, which is homologous to the core of the human metallothionein II metal-responsive element. The se- quences required for serum-stimulated transcription are dis- tinct from the heat shock element. The sequence CCAAT at -68 is required for high levels of correctly initiated transcripts, and a purine-rich sequence, GAAGGGAAAAG, at -58 is required for serum stimulation. The human HSP70 promoter contains at least two regulatory domains-a distal domain responsive to heat shock or cadmium and a proximal domain responsive to stimulation by serum.

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

Abstract: RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

Rapid, Long-Distance Electrical and Calcium Signaling in Plants

Abstract: Plants integrate activities throughout their bodies using long-range signaling systems in which stimuli sensed by just a few cells are translated into mobile signals that can influence the activities in distant tissues. Such signaling can travel at speeds well in excess of millimeters per second and can trigger responses as diverse as changes in transcription and translation levels, posttranslational regulation, alterations in metabolite levels, and even wholesale reprogramming of development. In addition to the use of mobile small molecules and hormones, electrical signals have long been known to propagate throughout the plant. This electrical signaling network has now been linked to waves of Ca(2+) and reactive oxygen species that traverse the plant and trigger systemic responses. Analysis of cell type specificity in signal propagation has revealed the movement of systemic signals through specific cell types, suggesting that a rapid signaling network may be hardwired into the architecture of the plant.

Increased global transcription activity as a mechanism of replication stress in cancer

Abstract: Cancer is a disease associated with genomic instability that often results from oncogene activation. This in turn leads to hyperproliferation and replication stress. However, the molecular mechanisms that underlie oncogene-induced replication stress are still poorly understood. Oncogenes such as HRASV12 promote proliferation by upregulating general transcription factors to stimulate RNA synthesis. Here we investigate whether this increase in transcription underlies oncogene-induced replication stress. We show that in cells overexpressing HRASV12, elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which together with R-loop accumulation results in replication fork slowing and DNA damage. Furthermore, overexpression of TBP alone causes the hallmarks of oncogene-induced replication stress, including replication fork slowing, DNA damage and senescence. Consequently, we reveal that increased transcription can be a mechanism of oncogene-induced DNA damage, providing a molecular link between upregulation of the transcription machinery and genomic instability in cancer.

Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage

Abstract: The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs). Strikingly, many DSBs that accumulate in response to E2 are R-loop dependent. Thus, R-loops resulting from the E2 transcriptional response are a significant source of DNA damage. This work reveals a novel mechanism by which E2 stimulation leads to genomic instability and highlights how transcriptional programs play an important role in shaping the genomic landscape of DNA damage susceptibility.

S1-DRIP-seq identifies high expression and polyA tracts as major contributors to R-loop formation

Abstract: R loops form when transcripts hybridize to homologous DNA on chromosomes, yielding a DNA:RNA hybrid and a displaced DNA single strand. R loops impact the genome of many organisms, regulating chromosome stability, gene expression, and DNA repair. Understanding the parameters dictating R-loop formation in vivo has been hampered by the limited quantitative and spatial resolution of current genomic strategies for mapping R loops. We report a novel whole-genome method, S1-DRIP-seq (S1 nuclease DNA:RNA immunoprecipitation with deep sequencing), for mapping hybrid-prone regions in budding yeast Saccharomyces cerevisiae Using this methodology, we identified ∼800 hybrid-prone regions covering 8% of the genome. Given the pervasive transcription of the yeast genome, this result suggests that R-loop formation is dictated by characteristics of the DNA, RNA, and/or chromatin. We successfully identified two features highly predictive of hybrid formation: high transcription and long homopolymeric dA:dT tracts. These accounted for >60% of the hybrid regions found in the genome. We demonstrated that these two factors play a causal role in hybrid formation by genetic manipulation. Thus, the hybrid map generated by S1-DRIP-seq led to the identification of the first global genomic features causal for R-loop formation in yeast.

RNA Polymerase II cluster dynamics predict mRNA output in living cells

Abstract: Protein clustering is a hallmark of genome regulation in mammalian cells. However, the dynamic molecular processes involved make it difficult to correlate clustering with functional consequences in vivo. We developed a live-cell super-resolution approach to uncover the correlation between mRNA synthesis and the dynamics of RNA Polymerase II (Pol II) clusters at a gene locus. For endogenous β-actin genes in mouse embryonic fibroblasts, we observe that short-lived (~8 s) Pol II clusters correlate with basal mRNA output. During serum stimulation, a stereotyped increase in Pol II cluster lifetime correlates with a proportionate increase in the number of mRNAs synthesized. Our findings suggest that transient clustering of Pol II may constitute a pre-transcriptional regulatory event that predictably modulates nascent mRNA output.

The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan

Abstract: Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.