Mechanistic insights into allele-specific properties of inter-chromosomal contacts
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE99657 | GEO | 2019/01/31
REPOSITORIES: GEO
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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.
2018-02-12 | GSE104814 | GEO
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.
2018-02-12 | GSE104427 | GEO
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.
2018-02-12 | GSE104367 | GEO
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:ABSTRACT 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 may play roles in establishing TAD boundary formation. This SuperSeries is composed of the SubSeries listed below.
2018-02-12 | GSE98632 | GEO
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: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 protein-binding or histone modification profiles in Patski cells.
2015-02-26 | E-GEOD-66262 | biostudies-arrayexpress
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: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: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.
2013-06-01 | GSE45157 | GEO