Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1254742 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33305002_1.fastq.gz | Fastqsanger.gz | |||
| SRR33305002_2.fastq.gz | Fastqsanger.gz | |||
| SRR33301182_1.fastq.gz | Fastqsanger.gz | |||
| SRR33301182_2.fastq.gz | Fastqsanger.gz | |||
| SRR33301183_1.fastq.gz | Fastqsanger.gz |
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Project description:p53 executes its diverse functions via different transcriptional targets, but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify PURB, a dual DNA/RNA-binding protein, that acts as a transcriptional co-repressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers while its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and Mdm2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with lncRNA HOTAIR to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB/HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets indicates a number of promoters that may serve as a target for PURB-binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB-HOTAIR complex.
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Project description:p53 executes its diverse functions via different transcriptional targets, but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify PURB, a dual DNA/RNA-binding protein, that acts as a transcriptional co-repressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers while its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and Mdm2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with lncRNA HOTAIR to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB/HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets indicates a number of promoters that may serve as a target for PURB-binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB-HOTAIR complex.
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Project description:Here we identify PURB, a dual DNA/RNA-binding protein, as a key mediator for LncRNAs to interact with p53. PURB is overexpressed in human cancers and loss of PURB expression in human cancer cells induces tumor growth suppression by activating p53. Interestingly, PURB knockdown activates only a subset of p53 target genes without affecting p53 protein levels and PURB is specifically recruited by p53 to the target genes in a promoter-specific manner. Moreover, a unique cis-regulatory element is identified at the target promoters recognized by PURB; loss of this element does not affect p53-mediated transactivation but abrogates the ability of p53 to recruit PURB to the promoters for repression. Notably, the ability of PURB in transcriptional repression requires its sequence-specific binding with HOTAIR, one of LncRNAs tightly associated with PURB. HOTAIR interacts directly with SUV39H1 and, bridging by the PURB/HOTAIR complex, p53 is able to recruit SUV39H1 histone methyltransferase to the target promoters for transcriptional repression. These data establish a new mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and also reveal, a previously unanticipated mechanism for promoter-specific regulation through a unique cis-regulatory element recognized by the LncRNA-protein complex.
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Project description:The human long noncoding RNA (lncRNA) HOTAIR acts in trans to recruit the Polycomb Repressive Complex 2 (PRC2) to the HOXD gene cluster and promote gene silencing during development. In breast cancers, overexpression of HOTAIR increases metastatic potential via the repression of many additional genes. It has remained unclear what factors determine HOTAIR-dependent PRC2 activity at specific genomic loci, particularly when high levels of HOTAIR result in aberrant gene silencing. To identify additional proteins that contribute to the specific action of HOTAIR, we performed a quantitative proteomic analysis of the HOTAIR interactome. We found that the most specific interaction was between HOTAIR and the heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, a member of a family of proteins involved in nascent mRNA processing and RNA matchmaking. Our data suggest that A2/B1 are key contributors to HOTAIR-mediated chromatin regulation in breast cancer cells: A2/B1 knockdown reduces HOTAIR-dependent breast cancer cell invasion and decreases PRC2 activity at the majority of HOTAIR-dependent loci. We found that the B1 isoform, which differs from A2 by 12 additional amino acids, binds with highest specificity to HOTAIR. B1 also binds chromatin and associates preferentially with RNA transcripts of HOTAIR gene targets. We furthermore demonstrate a direct RNA-RNA interaction between HOTAIR and a target transcript that is enhanced by B1 binding. Together, these results suggest a model in which B1 matches HOTAIR with transcripts of target genes on chromatin, leading to repression by PRC2.
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Project description:Mechanisms governing regional human adipose tissue (AT) development remain undefined. Here, we show that the long non-coding RNA, HOTAIR (HOX transcript antisense RNA), is exclusively expressed in gluteofemoral AT, where it is essential for adipocyte development. We find that HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and identify core HOTAIR-PRC2 target genes involved in adipocyte lineage determination. Repression of target genes coincides with PRC2 promoter occupancy and H3K27 tri-methylation. HOTAIR is also involved in modifying the gluteal adipocyte transcriptome through alternative splicing. Gluteal-specific expression of HOTAIR is maintained by defined regions of open chromatin across the HOTAIR promoter. HOTAIR expression levels can be modified by hormonal (oestrogen, glucocorticoids) and genetic variation (rs1443512 is a HOTAIR eQTL associated with reduced gynoid fat mass in 25,200 individuals). These data identify HOTAIR as a dynamic regulator of the gluteal adipocyte transcriptome and epigenome with functional importance for human regional AT development.
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Project description:Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood4,5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodeling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb Repressive Complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings suggest that lincRNAs play active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy. Comparision of MDA-MB-231 Breast Cancer Cells expressing vector or HOTAIR. Each cell line was subjected to ChIP-chip with anti-H3K27, SUZ12, and EZH2 and interrogated on whole genome promoter arrays
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