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Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence

ABSTRACT: Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence

PROVIDER: PRJNA432582 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6663640_1.fastq.gz	Fastqsanger.gz
	SRR6663640_2.fastq.gz	Fastqsanger.gz
	SRR6663650_1.fastq.gz	Fastqsanger.gz
	SRR6663650_2.fastq.gz	Fastqsanger.gz
	SRR6663660_1.fastq.gz	Fastqsanger.gz

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Deregulated expression of mammalian lncRNA through loss of SPT6 induces R-loop formation, replication stress and cellular senescence

Project description:Extensive tracts of the mammalian genome that lack protein-coding function are still transcribed into long noncoding RNA. While these lncRNA are generally short-lived, length-restricted and non-polyadenylated, how their expression is distinguished from protein-coding genes remains enigmatic. Surprisingly depletion of the ubiquitous Pol II associated transcription elongation factor SPT6, promotes a redistribution of H3K36me3 histone marks from active protein coding to lncRNA genes which correlates with increased lncRNA transcription. SPT6 knockdown also impairs the recruitment of Integrator complex to chromatin which results in a transcriptional termination defect for lncRNA genes. This leads to the formation of extended, polyadenylated lncRNA that are both chromatin restricted and form increased levels of RNA:DNA hybrid (R-loops) that are associated with DNA damage. Additionally, these deregulated lncRNA overlap with DNA replication origins leading to localized DNA replication stress and a cellular senescence phenotype. Overall our results underline the importance of restricting lncRNA expression.

2018-11-15 | GSE120371 | GEO

Deregulated expression of mammalian lncRNA through loss of SPT6 induces R-loop formation, replication stress and cellular senescence

Project description:Deregulated expression of mammalian lncRNA through loss of SPT6 induces R-loop formation, replication stress and cellular senescence

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Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence

Project description:RNA polymerase II (Pol II) generates interspersed protein-coding and long noncoding (lnc) transcripts across the mammalian genome. We recently established that lncRNAs are transcribed by different Pol II CTD isoforms correlating with reduced RNA processing efficiency and increased RNA turnover. How protein-coding and lncRNA transcription units are distinguished during gene expression remains unclear. We now show that H3K36me3 chromatin is a predominant epigenetic mark for active protein-coding but not lncRNA genes. Surprisingly depletion of the Pol II associated transcription elongation factor SPT6, causes redistribution of H3K36me3 histone marks to lncRNA genes which correlates with increased lncRNA transcription. SPT6 knockdown also reduces recruitment of Integrator complex to chromatin resulting in a transcription termination defect for lncRNA genes. Notably these extended lncRNAs are both chromatin-restricted and form increased levels of RNA:DNA hybrid (R-loops) with associated DNA damage. This results in a cellular senescence phenotype and underlies the importance of restricting lncRNA expression.

2018-11-21 | GSE110028 | GEO

Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence.

Project description:Extensive tracts of the mammalian genome that lack protein-coding function are still transcribed into long noncoding RNA. While these lncRNAs are generally short lived, length restricted, and non-polyadenylated, how their expression is distinguished from protein-coding genes remains enigmatic. Surprisingly, depletion of the ubiquitous Pol-II-associated transcription elongation factor SPT6 promotes a redistribution of H3K36me3 histone marks from active protein coding to lncRNA genes, which correlates with increased lncRNA transcription. SPT6 knockdown also impairs the recruitment of the Integrator complex to chromatin, which results in a transcriptional termination defect for lncRNA genes. This leads to the formation of extended, polyadenylated lncRNAs that are both chromatin restricted and form increased levels of RNA:DNA hybrid (R-loops) that are associated with DNA damage. Additionally, these deregulated lncRNAs overlap with DNA replication origins leading to localized DNA replication stress and a cellular senescence phenotype. Overall, our results underline the importance of restricting lncRNA expression.

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The conserved histone chaperone Spt6 facilitates DNA replication and mediates genome stability [MCM ChIPseq]

Project description:Histone chaperones are an important class of factors that regulate chromatin accessibility for DNA-templated processes. Spt6 is a conserved histone chaperone and key regulator of transcription and chromatin structure. However, its functions outside of these roles have been little explored. In this work, we demonstrate a role for Spt6 in DNA replication and more broadly as a regulator of genome stability. Spt6 binds the replication machinery and mutations or loss of Spt6 impair DNA replication in vivo. Additionally, spt6 mutants are sensitive to DNA replication stress inducing agents, with increased sensitivity when combined with loss of DNA replication associated factors. Furthermore, spt6 mutants have elevated levels of DNA double strand breaks and are hyper-recombinogenic. R-loops do not appear to be elevated in spt6 mutants. In total, we identify Spt6 as a regulator of genome stability, at least in part through a role for Spt6 in DNA replication.

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The conserved histone chaperone Spt6 facilitates DNA replication and mediates genome instability [BrdU-IP-seq]

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The conserved histone chaperone Spt6 facilitates DNA replication and mediates genome instability [S1-DRIP-seq]

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Casein Kinase II Phosphorylation of Spt6 Enforces Transcriptional Fidelity by Maintaining Spn1-Spt6 Interaction

Project description:Spt6 is a histone chaperone that associates with RNA polymerase II and deposits nucleosomes in the wake of transcription. Although Spt6 has an essential function in nucleosome deposition, it is not known whether this function is regulated by post-translational modification. Here, we report that casein kinase II (CKII) phosphorylation of Spt6 directs nucleosome reassembly at the 5’ ends of a broad range of genes to prevent aberrant antisense transcription and enforce transcriptional directionality. Mechanistically, we show that interaction of Spt6 with Spn1 – a constitutive binding partner required for chromatin reassembly and full recruitment of Spt6 to genes is positively regulated by CKII phosphorylation of Spt6. Together, our study defines a previously unknown function for CKII phosphorylation in transcription, and further, highlights the importance of post-translational modification as a mechanism to fine-tune the functions of histone chaperones.

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RNA Polymerase II interactome in presence or absence of SPT6 in U2OS cells

Project description:SPT6 is a histone chaperone that tightly binds RNA polymerase II (POL2) during transcription elongation. However, its primary role in POL2 transcription is uncertain. We used targeted protein degradation to rapidly deplete SPT6 in human cells and analyzed defects in POL2 behavior by a multi-omics approach and mathematical modeling. Our data indicate that SPT6 is a crucial factor for POL2 processivity and is therefore required for the productive transcription of protein-coding genes. Unexpectedly, SPT6 also has a vital role in POL2 termination, as acute depletion induced readthrough transcription for thousands of genes. Long-term depletion of SPT6 induced cryptic intragenic transcription, as observed earlier in yeast. However, this phenotype was not observed upon acute SPT6 depletion and therefore can be attributed to accumulated epigenetic perturbations in the absence of SPT6. In conclusion, targeted protein degradation of SPT6 allowed the temporal discrimination of its function as an epigenetic safeguard and POL2 elongation factor.

2021-06-28 | PXD025243 | Pride

Analysis of RNA polymerase II interacting proteins in wild-type and spt6-1004 yeast cells.

Project description:The histone chaperone Spt6 is involved in promoting elongation of RNA polymerase II (RNAPII), maintaining chromatin structure, regulating co-transcriptional histone modifications, and controlling mRNA processing. These diverse functions of Spt6 are partly mediated through its interactions with RNAPII and other factors in the transcription elongation complex. In this study, we used mass spectrometry to characterize the differences in RNAPII interacting factors between wild-type cells and those depleted for Spt6, leading to the identification of proteins that depend on Spt6 for their interaction with RNAPII. In all, eight samples were processed - four genotypes (1. SPT6, RPB3-untagged; 2. SPT6, RPB3-tagged; 3. spt6-1004, RPB3-untagged; 4. spt6-1004; RPB3-tagged) in biological duplicates.

2021-12-05 | PXD027708 | Pride

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