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P53 transcription factor mediates nuclear speckle association of target genes

ABSTRACT: Nuclear speckles are prominent nuclear bodies that contain a myriad of factors involved in gene expression. The role of nuclear speckles as activating transcriptional compartments is emerging. However, the extent that the association between speckles and DNA is regulatable, and the mechanisms that govern regulated speckle association are currently unclear. Using DNA- and RNA-FISH, we show that speckle association can be mediated by the p53 transcription factor, finding that p53 activation drives speckle association of specific p53 transcriptional targets. Analysis of a key p53 target, p21, revealed an increase in nascent transcripts at speckle-adjacent transcription sites, supporting a role for speckles in amplifying transcriptional output. Importantly, p53-regulated speckle association of p21 did not depend on transcriptional activation, demonstrating that speckle association is not merely a consequence of gene expression. In contrast, speckle association of p21 did require DNA binding functions of p53, providing a mechanism for the specificity by which speckle association is regulated. Beyond p21, a substantial subset of p53 targets have p53-regulated speckle association, while other p53 targets do not, and we find that genomic context is highly deterministic of which target genes have regulated speckle association. These findings reveal a novel means by which transcription factors may control gene expression and provide a mechanism for the specificity of regulated speckle association.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154095 | GEO | 2021/01/04

REPOSITORIES: GEO

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Project description:Recently, more than a thousand large intergenic non-coding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediated apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulating their localization to sets of previously active genes. Gene expression profiles of different p53 inducible mouse embryonic fibroblasts (p53LSL/LSL MEFs) across different time points after DNA damage. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 transcriptional response. [1] MEF profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration or adenoGFP as control for 24h and treated with 500nM doxorubicin for the indicated times. [2] hnRNPKKD profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration for 24h, transfected with siRNA oligos targeting different transcripts for 24h and then treated with 100nM doxorubicin for 13h. [3] lincP21KD profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration for 24h, transfected with siRNA oligos targeting different transcripts for 24h and then treated with 100nM doxorubicin for 13h. [4] RAS profiling: For p53 restoration, cultured tumor cell lines were incubated with 500nM 4-hydroxytamoxifen for the indicated times.

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P53 transcription factor mediates nuclear speckle association of target genes

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