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The lncRNA Firre functions as a rapid regulator of transcription from a distance [ChIP-Seq]

ABSTRACT: There are currently over 16,000 long-noncoding RNAs (lncRNAs) annotated in mammalian genomes, a number on par with protein-coding genes. Numerous studies have demonstrated that lncRNAs can influence gene expression programs but lack the temporal resolution to identify the immediate regulatory events. Thus, even for the most well-studied lncRNAs, the early and primary targets remain elusive, even though they are a prerequisite to elucidating lncRNA mechanisms. Here we describe a multifaceted effort to determine the primary targets of a lncRNA and the underlying temporal dynamics. We combine several genetically defined loss- and gain-of-function, rescue, and inducible lncRNA models to resolve gene regulatory events temporally from 30 minutes to four days. Applying this approach, we find that in mouse ES cells, the lncRNA Firre regulates the expression of 29 high-confidence target genes. Firre-regulated gene expression is not mediated by epigenetic events nor the proximal binding of the Firre lncRNA to its target genes. Instead, Firre induces nascent transcription and increases chromatin accessibility within minutes, resulting in mature transcripts of the primary target genes about an hour later. Overall, this study suggests Firre functions as a rapid RNA-based transcriptional regulator from a distance.

ORGANISM(S): Mus musculus

PROVIDER: GSE216144 | GEO | 2024/03/01

REPOSITORIES: GEO

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The Firre lncRNA acts as a transcriptional activator [PRO-Seq]

Project description:There are currently over 16,000 long-noncoding RNAs (lncRNAs) annotated in mammalian genomes, a number on par with protein-coding genes. Numerous studies have demonstrated that lncRNAs can influence gene expression programs but lack the temporal resolution to identify the immediate regulatory events. Thus, even for the most well studied the early and primary targets of lncRNAs remains elusive. Here we describe a multifaceted effort to determine the primary targets of a lncRNA and the underlying temporal dynamics. Our approach combines several genetically defined loss-of and gain-of-function, rescue, and inducible lncRNA models. We further resolved gene regulatory events temporally (30 min to four days). Applying this approach, we find that the lncRNA Firre is an RNA-based transcriptional activator. These transcriptional activation events are not mediated by the epigenetic regulators PRC2, WDR5, or G9A, nor are they due to the proximal binding of the Firre lncRNA. Instead, Firre activates transcription by increasing chromatin accessibility (approximately 30 min after induction) and activating primary target genes (about an hour later). Overall, this study suggests Firre functions as an RNA-based transcriptional activator.

2024-03-01 | GSE216145 | GEO

The lncRNA Firre functions as a rapid regulator of transcription [RNA-seq]

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Evolutionary divergence of Firre localization and expression

Project description:Long non-coding RNAs (lncRNAs) are rapidly evolving and thus typically poorly conserved in their sequences. The extent to which these sequence differences affect the characteristics and potential functions of lncRNAs with shared synteny remains unclear. Here we show that the syntenically conserved lncRNA Firre displays distinct expression and localization patterns in human and mouse. Single molecule RNA FISH reveals that in a range of cell lines, mouse Firre (mFirre) is predominantly nuclear, while human FIRRE (hFIRRE) is distributed between the cytoplasm and nucleus. This localization pattern is maintained in human/mouse hybrid cells expressing both human and mouse Firre, implying that the localization of the lncRNA is species autonomous. We find that the majority of hFIRRE transcripts in the cytoplasm are comprised of isoforms that are enriched in RRD repeats. We furthermore determine that in various tissues, mFirre is more highly expressed than its human counterpart. Our data illustrate that the rapid evolution of syntenic lncRNAs can lead to variations in lncRNA localization and abundance, which in turn may result in disparate lncRNA functions even in closely related species.

2022-04-19 | GSE186876 | GEO

Effects of Firre knockdown on mouse gene expression

Project description:In mammals, genes located on the X chromosome are present in one copy in XY males and two in XX females. To balance the dosage of X-linked gene expression between the sexes one of the two X chromosomes in females is silenced by X inactivation initiated by up-regulation of the lncRNA (long non-coding RNA) Xist and recruitment of specific chromatin modifiers for silencing. The inactivated X chromosome becomes heterochromatic and visits a specific nuclear compartment adjacent to the nucleolus. We report a novel role for the X-linked lncRNA Firre in anchoring the inactive mouse X chromosome and preserving one of its main epigenetic features, trimethylation of histone H3 at lysine 27 (H3K27me3). Similar to Dxz4, Firre is expressed from a macrosatellite repeat locus associated with a cluster of CTCF and cohesin binding specifically on the inactive X. CTCF binding initially present in both male and female mouse embryonic stem cells was found to be lost from the active X during development. The Firre and Dxz4 loci on the inactive X were preferentially located adjacent to the nucleolus. Knockdown of Firre RNA disrupted perinucleolar targeting and H3K27me3 levels in mouse fibroblasts, demonstrating an important role for this lncRNA in maintenance of one of the main epigenetic features of the X chromosome. There was no X-linked gene reactivation after Firre knockdown; however, a compensatory increase in the expression of chromatin modifier genes implicated in X silencing was observed. In female ES cells Firre RNA knockdown did not disrupt Xist expression/coating nor silencing of G6pdx during differentiation, suggesting that Firre does not play a role in the onset of X inactivation. We conclude that the X-linked lncRNA Firre helps position the inactive X chromosome near the nucleolus and preserve one of its main epigenetic features. Examination of allelic expression in Patski cells upon Firre knockdown.

2015-03-05 | E-GEOD-66172 | biostudies-arrayexpress

Effects of Firre knockdown on mouse gene expression

2015-03-05 | GSE66172 | GEO

The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis

Project description:We used the Functional intergenic repeating RNA element (Firre) locus - a conserved intergenic lncRNA gene that is located on the X chromosome11,12 - as a model to discriminate DNA- and RNA-mediated effects in vivo. Using genetically defined loss-of-function, gain-of-function, and rescue mouse models for Firre, we identify cell-specific defects during hematopoiesis and immune function. This includes impaired survival upon lipopolysaccharide challenge and diminished production of immune cells in Firre knockout mice. We show that these defects can be rescued by induction of Firre RNA from a transgene in the Firre knockout background. Moreover, upon ectopic induction of Firre expression, we observe an in vivo rescue of gene expression programs that were lost in the Firre knockout model. Finally, we show that unlike most regulatory DNA and RNA species, which function locally to regulate the expression of neighboring genes, Firre RNA acts in trans to alter cellular functions.

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A TAD boundary is preserved upon deletion of the CTCF-rich Firre locus [HiC_mESC]

Project description:The binding of the transcriptional regulator CTCF to the genome has been implicated in the formation of topologically associated domains (TADs). However, the general mechanisms of folding the genome into TADs are not fully understood. Here, we tested the effects of deleting a CTCF-rich locus on TAD boundary formation. Using genome-wide chromosome conformation capture (Hi-C), we focus on one TAD boundary on chromosome X harboring ~15 CTCF binding sites, and located at the long non-coding RNA (lncRNA) locus Firre. Specifically, this TAD boundary is invariant across evolution, tissues, and temporal dynamics of X-chromosome inactivation. We demonstrate that neither the deletion of this locus, nor the ectopic insertion of Firre cDNA or its ectopic expression are sufficient to alter TADs in a sex-, or allele-specific manner. In contrast, Firre’s deletion disrupts the chromatin super-loop formation of the inactive X-chromosome. Collectively, our findings suggest that apart from CTCF binding, additional mechanisms can play roles in establishing TAD boundary formation.

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A TAD boundary is preserved upon deletion of the CTCF-rich Firre locus [HiC_MEF]

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X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes

Project description:The lncRNA Crossfirre was identified as an imprinted X-linked gene, and is transcribed antisense to the trans-acting lncRNA Firre. The Firre locus forms an inactive-X-specific interaction with Dxz4, both loci providing the platform for the largest conserved chromatin structures. Here, we characterized the epigenetic profile of these loci, revealing them as the most female-specific accessible regions genome-wide. To address their in vivo role, we performed one of the largest X-linked knockout studies by deleting Crossfirre, Firre, and Dxz4 individually and in combination (TKO). Despite their distinct epigenetic features observed on the X chromosome, our allele-specific analysis uncovers these loci as dispensable for imprinted and random X chromosome inactivation. However, we provide evidence that Crossfirre affects autosomal gene regulation but only in combination with Firre. To shed light on the functional role of these sex-specific loci, we performed an extensive standardized phenotyping pipeline and uncovered diverse knockout and sex-specific phenotypes. Collectively, our study provides the foundation for exploring the intricate interplay of conserved X-linked loci in vivo.

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