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P53 directly represses human LINE1 transposons.

ABSTRACT: p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germline tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5'UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.

SUBMITTER: Tiwari B

PROVIDER: S-EPMC7608743 | biostudies-literature |

REPOSITORIES: biostudies-literature

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p53 directly represses human LINE1 transposons

Project description:p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germ line tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5’UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.

2020-12-01 | GSE159134 | GEO

p53 directly represses human LINE1 transposons

Project description:p53 directly represses human LINE1 transposons

| PRJNA667740 | ENA

p53 directly represses Id2 to inhibit the proliferation of neural progenitor cells.

Project description:Neural progenitor cells (NPCs) have the capacity to proliferate and give rise to all major central nervous system cell types and represent a possible cell of origin in gliomagenesis. Deletion of the tumor suppressor gene Tp53 (p53) results in increased proliferation and self-renewal of NPCs and is a common genetic mutation found in glioma. We have identified inhibitor of DNA binding 2 (Id2) as a novel target gene directly repressed by p53 to maintain normal NPC proliferation. p53((-/-)) NPCs express elevated levels of Id2 and suppression of Id2 expression is sufficient to inhibit the increased proliferation and self-renewal which results from p53 loss. Elevated expression of Id2 in wild-type NPCs phenocopies the behavior of p53((-/-)) NPCs by enhancing NPC proliferation and self-renewal. Interestingly, p53 directly binds to a conserved site within the Id2 promoter to mediate these effects. Finally, we have identified elevated Id2 expression in glioma cell lines with mutated p53 and demonstrated that constitutive expression of Id2 plays a key role in the proliferation of glioma stem-like cells. These findings indicate that Id2 functions as a proproliferative gene that antagonizes p53-mediated cell cycle regulation in NPCs and may contribute to the malignant proliferation of glioma-derived tumor stem cells.

| S-EPMC3647692 | biostudies-literature

Coprs inactivation leads to a derepression of <i>LINE1</i> transposons in spermatocytes.

Project description:Repression of retrotransposons is essential for genome integrity during germ cell development and is tightly controlled through epigenetic mechanisms. In primordial germ cells, protein arginine N-methyltransferase (Prmt5) is involved in retrotransposon repression by methylating Piwi proteins, which is part of the piRNA pathway. Here, we show that in mice, genetic inactivation of coprs (which is highly expressed in testis and encodes a histone-binding protein required for the targeting of Prmt5 activity) affects the maturation of spermatogonia to spermatids. Mass spectrometry analysis revealed the presence of Miwi in testis protein lysates immunoprecipitated with an anti-Coprs antibody. The observed deregulation of Miwi and pachytene pre-piRNAs levels and the derepression of LINE1 repetitive sequences observed in coprs-/- mice suggest that Coprs is implicated in genome surveillance mechanisms.

| S-EPMC6325579 | biostudies-literature

SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age.

Project description:L1 retrotransposons are an abundant class of transposable elements that pose a threat to genome stability and may have a role in age-related pathologies such as cancer. Recent evidence indicates that L1s become more active in somatic tissues during the course of ageing; however the mechanisms underlying this phenomenon remain unknown. Here we report that the longevity regulating protein, SIRT6, is a powerful repressor of L1 activity. Specifically, SIRT6 binds to the 5'-UTR of L1 loci, where it mono-ADP ribosylates the nuclear corepressor protein, KAP1, and facilitates KAP1 interaction with the heterochromatin factor, HP1α, thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin. During the course of ageing, and also in response to DNA damage, however, we find that SIRT6 is depleted from L1 loci, allowing the activation of these previously silenced retroelements.

| S-EPMC4185372 | biostudies-literature

Replicative Senescence-Associated LINE1 Methylation and LINE1-Alu Expression Levels in Human Endothelial Cells.

Project description:One of the main challenges of current research on aging is to identify the complex epigenetic mechanisms involved in the acquisition of the cellular senescent phenotype. Despite some evidence suggested that epigenetic changes of DNA repetitive elements, including transposable elements (TE) sequences, are associated with replicative senescence of fibroblasts, data on different types of cells are scarce. We previously analysed genome-wide DNA methylation of young and replicative senescent human endothelial cells (HUVECs), highlighting increased levels of demethylated sequences in senescent cells. Here, we aligned the most significantly demethylated single CpG sites to the reference genome and annotated their localization inside TE sequences and found a significant hypomethylation of sequences belonging to the Long-Interspersed Element-1 (LINE-1 or L1) subfamilies L1M, L1P, and L1HS. To verify the hypothesis that L1 demethylation could be associated with increased transcription/activation of L1s and/or Alu elements (non-autonomous retroelements that usually depend on L1 sequences for reverse transcription and retrotransposition), we quantified the RNA expression levels of both L1 (generic L1 elements or site-specific L1PA2 on chromosome 14) and Alu elements in young and senescent HUVECs and human dermal fibroblasts (NHDFs). The RNA expression of Alu and L1 sequences was significantly increased in both senescent HUVECs and NHDFs, whereas the RNA transcript of L1PA2 on chromosome 14 was not significantly modulated in senescent cells. Moreover, we found an increased amount of TE DNA copies in the cytoplasm of senescent HUVECs and NHDFs. Our results support the hypothesis that TE, which are significantly increased in senescent cells, could be retrotranscribed to DNA sequences.

| S-EPMC9739197 | biostudies-literature

miR-503 represses human cell proliferation and directly targets the oncogene DDHD2 by non-canonical target pairing.

Project description:BackgroundThe pathways regulating the transition of mammalian cells from quiescence to proliferation are mediated by multiple miRNAs. Despite significant improvements in our understanding of miRNA targeting, the majority of miRNA regulatory networks are still largely unknown and require experimental validation.ResultsHere we identified miR-503, miR-103, and miR-494 as negative regulators of proliferation in primary human cells. We experimentally determined their genome wide target profiles using RNA-induced silencing complex (RISC) immunoprecipitations and gene expression profiling. Analysis of the genome wide target profiles revealed evidence of extensive regulation of gene expression through non-canonical target pairing by miR-503. We identified the proto-oncogene DDHD2 as a target of miR-503 that requires pairing outside of the canonical 5' seed region of miR-503, representing a novel mode of miRNA-target pairing. Further bioinformatics analysis implicated miR-503 and DDHD2 in breast cancer tumorigenesis.ConclusionsOur results provide an extensive genome wide set of targets for miR-503, miR-103, and miR-494, and suggest that miR-503 may act as a tumor suppressor in breast cancer by its direct non-canonical targeting of DDHD2.

| S-EPMC4326481 | biostudies-literature

Menin directly represses Gli1 expression independent of canonical Hedgehog signaling.

Project description:Multiple endocrine neoplasia type 1 (MEN-1), is a familial tumor syndrome resulting from mutations in the tumor suppressor gene menin (MEN1). Menin plays an essential role in both repressing and activating gene expression. However, it is not well understood how menin represses expression of multiple genes. Upon MEN1 excision, the transcription factor Gli1 and its target genes, including Ptch1 and c-Myc, were shown to be elevated in the absence of an apparent Hedgehog) pathway-activating ligand or when Smoothened (SMO), a key component of the pathway, is inhibited. Menin binds to the GLI1 promoter and recruits PRMT5, a histone arginine methyltransferase associated with transcriptional repression. Both PRMT5 binding and histone H4 arginine 3 methylation (H4R3m2s) are decreased at the GLI1 promoter in MEN1-excised cells. Moreover, MEN1 ablation resulted in increased binding of transcriptionally active Gli1 at the GLI1 promoter in a manner not influenced by the canonical Hedgehog signaling pathway. Inhibition of Gli1 by the small-molecule inhibitor GANT-61 led to decreased expression of Gli1 and its target genes in MEN1-depeleted cells. Furthermore, GANT-61 potently suppressed proliferation of MEN1-excised cells as compared with control cells. These findings uncover a novel epigenetic link whereby menin directly represses Gli1 expression, independent of the canonical Hedgehog signaling pathway, via PRMT5 and its repressive H4R3m2s mark.Inhibition of GLI1 suppresses neuroendocrine tumors harboring mutations in the MEN1 gene.

| S-EPMC4028077 | biostudies-literature

p27(Kip1) directly represses Sox2 during embryonic stem cell differentiation.

Project description:The mechanisms responsible for the transcriptional silencing of pluripotency genes in differentiated cells are poorly understood. We have observed that cells lacking the tumor suppressor p27 can be reprogrammed into induced pluripotent stem cells (iPSCs) in the absence of ectopic Sox2. Interestingly, cells and tissues from p27 null mice, including brain, lung, and retina, present an elevated basal expression of Sox2, suggesting that p27 contributes to the repression of Sox2. Furthermore, p27 null iPSCs fail to fully repress Sox2 upon differentiation. Mechanistically, we have found that upon differentiation p27 associates to the SRR2 enhancer of the Sox2 gene together with a p130-E2F4-SIN3A repressive complex. Finally, Sox2 haploinsufficiency genetically rescues some of the phenotypes characteristic of p27 null mice, including gigantism, pituitary hyperplasia, pituitary tumors, and retinal defects. Collectively, these results demonstrate an unprecedented connection between p27 and Sox2 relevant for reprogramming and cancer and for understanding human pathologies associated with p27 germline mutations.

| S-EPMC3549496 | biostudies-literature

Inhibition of p53 acetylation by INHAT subunit SET/TAF-Iβ represses p53 activity.

Project description:The tumor suppressor p53 responds to a wide variety of cellular stress signals. Among potential regulatory pathways, post-translational modifications such as acetylation by CBP/p300 and PCAF have been suggested for modulation of p53 activity. However, exactly how p53 acetylation is modulated remains poorly understood. Here, we found that SET/TAF-Iβ inhibited p300- and PCAF-mediated p53 acetylation in an INHAT (inhibitor of histone acetyltransferase) domain-dependent manner. SET/TAF-Iβ interacted with p53 and repressed transcription of p53 target genes. Consequently, SET/TAF-Iβ blocked both p53-mediated cell cycle arrest and apoptosis in response to cellular stress. Using different apoptosis analyses, including FACS, TUNEL and BrdU incorporation assays, we also found that SET/TAF-Iβ induced cellular proliferation via inhibition of p53 acetylation. Furthermore, we observed that apoptotic Drosophila eye phenotype induced by either dp53 overexpression or UV irradiation was rescued by expression of dSet. Inhibition of dp53 acetylation by dSet was observed in both cases. Our findings provide new insights into the regulation of stress-induced p53 activation by HAT-inhibiting histone chaperone SET/TAF-Iβ.

| S-EPMC3245910 | biostudies-literature

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