Forced expression of MSR repeat transcripts breaks heterochromatin organization
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1091166 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28427100_1.fastq.gz | Fastqsanger.gz | |||
| SRR28427100_2.fastq.gz | Fastqsanger.gz | |||
| SRR28427101_1.fastq.gz | Fastqsanger.gz | |||
| SRR28427101_2.fastq.gz | Fastqsanger.gz | |||
| SRR28427102_1.fastq.gz | Fastqsanger.gz |
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Project description:Mouse heterochromatin is characterized by transcriptionally competent major satellite repeat (MSR) sequences and it has been proposed that MSR repeat RNA contributes to the integrity of heterochromatin. We established an inducible dCas9-effector system in mouse embryonic fibroblasts, where we can target dCas9-VPR (transcriptional activator) and dCas9-KM (transcriptional repressor) to MSR repeat sequences. We show that induction of dCas9-VPR forces significant MSR RNA output, while induction of dCas9-KM silences MSR transcription. Both approaches perturb heterochromatin organization, where the dCas9-VPR leads to an immediate dispersion of heterochromatin and dCas9-KM induction results in a delayed aggregation of heterochromatin. MEF cells with the forced expression of MSR RNA are not viable and the defects in heterochromatin organization cannot be reverted. This study highlights the importance of restricting MSR RNA output to maintain heterochromatin integrity and also reveals that the structural organization of heterochromatin is governed by the transcriptional state of the underlying MSR repeats.
2025-03-23 | GSE262294 | GEO
Project description:Forced expression of MSR repeat transcripts above a threshold limit breaks heterochromatin organization
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Project description:Mouse heterochromatin is characterised by transcriptionally competent major satellite repeat (MSR) sequences and it has been proposed that MSR RNA contributes to the integrity of heterochromatin. We established an inducible dCas9-effector system in mouse embryonic fibroblasts, where we can modulate MSR transcription through the targeting of a dCas9-Repressor or a dCas9-Activator. With this system, we can define a threshold limit of >300-fold deregulation of MSR transcript levels, above which the structural organisation of heterochromatin becomes disrupted. MEF cells expressing MSR RNA above this threshold limit are not viable and the defects in heterochromatin organisation and chromosome segregation cannot be reverted. This study highlights the importance of restricting MSR RNA output to maintain heterochromatin integrity and relates MSR transcript levels to either physiological or pathological conditions. It also reveals that the structural organisation of heterochromatin is governed by the transcriptional chromatin state and associated MSR RNA of the MSR repeats.
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Project description:Heterochromatin defines a transcription-repressive chromatin state. In mouse cells, heterochromatin is associated with underlying arrays of A/T-rich, 234 bp DNA repeat elements, called the major satellite repeats (MaSat or MSR). We have examined > 18,000 copies of MSR repeat units in mouse ES cells and identified that heterochromatin is only formed at transcriptionally competent MSR variants. To directly dissect the function of MSR DNA, we inserted isolated MSR copies into an inert genomic region that is repeat- and gene-free. Insertion of three or more intact MSR units, but not one MSR unit, induced heterochromatic histone marks, recruitment of HP1 and incorporation of histone H1. Only transcriptionally competent MSR copies, but not permutated MSR variants or other DNA repeats, such as LINE1 5’UTR elements can form de novo heterochromatin. MSR-derived transcription is bi-directional and MSR driven transcripts are attenuated by the RNA polymerase II (RNAPII) associated Integrator complex. This study resolves a long-standing paradox between heterochromatic and euchromatic transcriptional activity and uncovers a DNA/RNA based logic for the establishment of heterochromatin in the mouse epigenome.
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Project description:Heterochromatin defines a transcription-repressive chromatin state. In mouse cells, heterochromatin is associated with underlying arrays of A/T-rich, 234 bp DNA repeat elements, called the major satellite repeats (MaSat or MSR). We have examined > 18,000 copies of MSR repeat units in mouse ES cells and identified that heterochromatin is only formed at transcriptionally competent MSR variants. To directly dissect the function of MSR DNA, we inserted isolated MSR copies into an inert genomic region that is repeat- and gene-free. Insertion of three or more intact MSR units, but not one MSR unit, induced heterochromatic histone marks, recruitment of HP1 and incorporation of histone H1. Only transcriptionally competent MSR copies, but not permutated MSR variants or other DNA repeats, such as LINE1 5’UTR elements can form de novo heterochromatin. MSR-derived transcription is bi-directional and MSR driven transcripts are attenuated by the RNA polymerase II (RNAPII) associated Integrator complex. This study resolves a long-standing paradox between heterochromatic and euchromatic transcriptional activity and uncovers a DNA/RNA based logic for the establishment of heterochromatin in the mouse epigenome.
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Project description:Heterochromatin defines a transcription-repressive chromatin state. In mouse cells, heterochromatin is associated with underlying arrays of A/T-rich, 234 bp DNA repeat elements, called the major satellite repeats (MaSat or MSR). We have examined > 18,000 copies of MSR repeat units in mouse ES cells and identified that heterochromatin is only formed at transcriptionally competent MSR variants. To directly dissect the function of MSR DNA, we inserted isolated MSR copies into an inert genomic region that is repeat- and gene-free. Insertion of three or more intact MSR units, but not one MSR unit, induced heterochromatic histone marks, recruitment of HP1 and incorporation of histone H1. Only transcriptionally competent MSR copies, but not permutated MSR variants or other DNA repeats, such as LINE1 5’UTR elements can form de novo heterochromatin. MSR-derived transcription is bi-directional and MSR driven transcripts are attenuated by the RNA polymerase II (RNAPII) associated Integrator complex. This study resolves a long-standing paradox between heterochromatic and euchromatic transcriptional activity and uncovers a DNA/RNA based logic for the establishment of heterochromatin in the mouse epigenome.
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Project description:Heterochromatin defines a transcription-repressive chromatin state. In mouse cells, heterochromatin is associated with underlying arrays of A/T-rich, 234 bp DNA repeat elements, called the major satellite repeats (MaSat or MSR). We have examined > 18,000 copies of MSR repeat units in mouse ES cells and identified that heterochromatin is only formed at transcriptionally competent MSR variants. To directly dissect the function of MSR DNA, we inserted isolated MSR copies into an inert genomic region that is repeat- and gene-free. Insertion of three or more intact MSR units, but not one MSR unit, induced heterochromatic histone marks, recruitment of HP1 and incorporation of histone H1. Only transcriptionally competent MSR copies, but not permutated MSR variants or other DNA repeats, such as LINE1 5’UTR elements can form de novo heterochromatin. MSR-derived transcription is bi-directional and MSR driven transcripts are attenuated by the RNA polymerase II (RNAPII) associated Integrator complex. These data link RNA processing of MSR transcripts by the Integrator with heterochromatin formation. This study resolves a long-standing paradox between heterochromatic and euchromatic transcriptional activity and uncovers a DNA/RNA based logic for the establishment of heterochromatin in the mouse epigenome.
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Project description:Heterochromatin has crucial functions in protecting genome integrity. In mouse cells, heterochromatin is characterized by A/T-rich, 234 bp DNA repeat arrays, called the major satellite repeats (MSR). We investigated MSR expression in response to a variety of stress conditions by using small molecule compounds. We identified the isoflavone genistein to selectively derepress MSR transcription but not that of other DNA repeat elements. Genistein is a natural compound that is frequently used in dietary supplements and has been associated with reducing cancer risk. A 24 hrs exposure of mouse embryonic fibroblasts (MEF) to genistein results in a more than 100-fold induction of MSR transcripts. This derepression depends on the activity of RNA polymerase II and requires a cycling G1 cell population. Blocking the cell cycle at the G2/M stage significantly attenuates genistein- mediated derepression of MSR transcription. Mechanistically, DNA topoisomerase poisons phenocopy the genistein-dependent desilencing of MSR expression. Together, these data suggest that MSR transcriptional response is guided by an altered topology of the underlying A/T-rich MSR DNA repeat arrays. In addition, the data reveal a novel function for genistein in derepressing MSR transcription that may contribute to the growth inhibitory and anticancer properties of this natural compound.
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Project description:Heterochromatin has crucial functions in protecting genome integrity. In mouse cells, heterochromatin is characterized by A/T-rich, 234 bp DNA repeat arrays, called the major satellite repeats (MSR). We investigated MSR expression in response to a variety of stress conditions by using small molecule compounds. We identified the isoflavone genistein to selectively derepress MSR transcription but not that of other DNA repeat elements. Genistein is a natural compound that is frequently used in dietary supplements and has been associated with reducing cancer risk. A 24 hrs exposure of mouse embryonic fibroblasts (MEF) to genistein results in a more than 100-fold induction of MSR transcripts. This derepression depends on the activity of RNA polymerase II and requires a cycling G1 cell population. Blocking the cell cycle at the G2/M stage significantly attenuates genistein- mediated derepression of MSR transcription. Mechanistically, DNA topoisomerase poisons phenocopy the genistein-dependent desilencing of MSR expression. Together, these data suggest that MSR transcriptional response is guided by an altered topology of the underlying A/T-rich MSR DNA repeat arrays. In addition, the data reveal a novel function for genistein in derepressing MSR transcription that may contribute to the growth inhibitory and anticancer properties of this natural compound.
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