The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis
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ABSTRACT:
PROVIDER: PRJNA517161 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8489570_1.fastq.gz | Fastqsanger.gz | |||
| SRR8489570_2.fastq.gz | Fastqsanger.gz | |||
| SRR8489580_1.fastq.gz | Fastqsanger.gz | |||
| SRR8489580_2.fastq.gz | Fastqsanger.gz | |||
| SRR8489590_1.fastq.gz | Fastqsanger.gz |
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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.
2019-10-03 | GSE125683 | GEO
Project description:Firre encodes a lncRNA involved in nuclear organization in mammals. Here we find that Firre RNA is transcribed from the active X chromosome (Xa) and exerts trans-acting effects on the inactive X chromosome (Xi). Allelic deletion of Firre on the Xa in a mouse hybrid fibroblast cell line results in a dramatic loss of the histone modification H3K27me3 and of components of the PRC2 complex on the Xi as well as the disruption of the perinucleolar location of the Xi. These features are measurably rescued by ectopic expression of a mouse or human Firre/FIRRE cDNA transgene, strongly supporting a conserved trans-acting role of the Firre transcript in maintaining the Xi heterochromatin environment. Surprisingly, CTCF occupancy is decreased on the Xi upon loss of Firre RNA, but is partially recovered by ectopic transgene expression, suggesting a functional link between Firre RNA and CTCF in maintenance of epigenetic features and/or location of the Xi. Loss of Firre RNA results in dysregulation of genes implicated in cell division and development, but not in reactivation of genes on the Xi, which retains its bipartite structure despite some changes in chromatin contact distribution. Allelic deletion or inversion of Firre on the Xi causes localized redistribution of chromatin contacts, apparently dependent on the orientation of CTCF binding sites clustered at the locus. Thus, the Firre locus and its RNA have roles in the maintenance of epigenetic features and structure of the Xi.
2020-05-07 | GSE134305 | GEO
Project description:RNA has been classically known to play central roles in biology, including maintaining telomeres, protein synthesis, and in sex chromosome compensation. While thousands of long noncoding RNAs (lncRNAs) have been identified, attributing RNA-based roles to lncRNA loci requires assessing whether phenotype(s) could be due to DNA regulatory elements, transcription, or the lncRNA. Here, we use the conserved X chromosome lncRNA locus Firre, as a model to discriminate between DNA- and RNA-mediated effects in vivo. We demonstrate that (i) Firre mutant mice have cell-specific hematopoietic phenotypes, and (ii) upon exposure to lipopolysaccharide, mice overexpressing Firre exhibit increased levels of pro-inflammatory cytokines and impaired survival. (iii) Deletion of Firre does not result in changes in local gene expression, but rather in changes on autosomes that can be rescued by expression of transgenic Firre RNA. Together, our results provide genetic evidence that the Firre locus produces a trans-acting lncRNA that has physiological roles in hematopoiesis.
| S-EPMC6853988 | biostudies-literature
Project description:Trans- and cis-acting effects of the lncRNA Firre on epigenetic and structural features of the inactive X chromosome [ChIP-seq]
| PRJNA554674 | ENA
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.
2024-10-28 | GSE219160 | GEO
Project description:Natural genetic variation can cause significant differences in gene expression, but little is known about the polymorphisms that affect gene regulation. We analyzed regulatory variation in a cross between laboratory and wild strains of Saccharomyces cerevisiae. Clustering and linkage analysis defined groups of coregulated genes and the loci involved in their regulation. Most expression differences mapped to trans-acting loci. Positional cloning and functional assays showed that polymorphisms in GPA1 and AMN1 affect expression of genes involved in pheromone response and daughter cell separation, respectively. We also asked whether particular classes of genes were more likely to contain trans-regulatory polymorphisms. Notably, transcription factors showed no enrichment, and trans-regulatory variation seems to be broadly dispersed across classes of genes with different molecular functions
2010-06-05 | E-GEOD-617 | biostudies-arrayexpress
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
Project description:Natural genetic variation can cause significant differences in gene expression, but little is known about the polymorphisms that affect gene regulation. We analyzed regulatory variation in a cross between laboratory and wild strains of Saccharomyces cerevisiae. Clustering and linkage analysis defined groups of coregulated genes and the loci involved in their regulation. Most expression differences mapped to trans-acting loci. Positional cloning and functional assays showed that polymorphisms in GPA1 and AMN1 affect expression of genes involved in pheromone response and daughter cell separation, respectively. We also asked whether particular classes of genes were more likely to contain trans-regulatory polymorphisms. Notably, transcription factors showed no enrichment, and trans-regulatory variation seems to be broadly dispersed across classes of genes with different molecular functions Keywords: other
2003-09-03 | GSE617 | GEO
Project description:Long noncoding RNAs (lncRNAs) have emerged as an important layer of genome regulation with common mechanistic themes including the formation of ribonucleoprotein complexes. Here, we present a novel X-linked lncRNA termed linc-Firre that escapes X-chromosome inactivation and forms trans-chromosomal interactions required for adipogenesis. Linc-Firre is exclusively nuclear and forms punctate expression foci on chromatin near its site of transcription on both X-chromosomes in human and mouse. Both the localization of linc-Firre and the association with the nuclear matrix protein hnRNPU require a conserved repeating RNA domain, R2D2. Collectively, these results reveal a lincRNA that escapes X-chromosome inactivation with a critical role in driving cell fate decisions by trans-chromosomal interactions. Replicate RNA-Seq analyses of oligo-mediated knockdowns of linc-FIRRE and hnRNPU in two different cellular contexts; HeLa cells and mouse embryonic stem cells.
2013-06-01 | E-GEOD-45157 | biostudies-arrayexpress
Project description:Mammalian genomes are pervasively transcribed into long noncoding RNAs (lncRNAs), whose functions and modes of action remain poorly understood. EPB41L4A-AS1 is an evolutionary conserved and broadly and highly expressed lncRNA that produces the H/ACA snoRNA SNORA13 from one of its introns. We studied the consequences of EPB41L4A-AS1 perturbation in breast cancer cells and found that it acts both in cis to enhance expression of the proximal EPB41L4A gene, and in trans by broadly regulating gene expression, including expression of snoRNAs, transcription of genes involved in nucleolar biology and the distribution of nucleolar proteins. These effects are phenocopied by loss of SUB1, an interactor of EPB41L4A-AS1 and are observed following transient perturbations of EPB41L4A-AS1 that do not affect steady-state SNORA13 levels. Exogenous expression of the full-length EPB41L4A-AS1 locus but not SNORA13 expression can rescue the trans-acting transcriptional effects of its perturbation. The EPB41L4A-AS1 gene is thus a versatile locus producing RNA molecules acting on multiple levels and important for key cellular functions.
2026-02-09 | GSE292272 | GEO