TargetGeneReg 2.0: a comprehensive web-atlas for p53, p63, and cell cycle-dependent gene regulation

Fischer, Martin; Schwarz, Robert; Riege, Konstantin; DeCaprio, James A.; Hoffmann, Steve

doi:10.1093/narcan/zcac009

Cited by 35 publications

(67 citation statements)

References 67 publications

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“…Furthermore, some other genes relatively high up in our list of upregulated genes upon MDMX depletion, including DDIT4, TP53INP1 and PNRC1, are reported as RFX7-target genes [ 69 ]. Based on these results, the website regarding p53-target genes was updated to TargetGeneReg 2.0 [ 70 ], including information on the RFX7 target genes. Therefore, we decided to investigate a possible involvement of RFX7 in our cell lines upon MDMX depletion.…”

Section: Resultsmentioning

confidence: 99%

MDMX Regulates Transcriptional Activity of p53 and FOXO Proteins to Stimulate Proliferation of Melanoma Cells

Heijkants

Teunisse

Jong

et al. 2022

Cancers

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The tumor suppressor protein p53 has an important role in cell-fate determination. In cancer cells, the activity of p53 is frequently repressed by high levels of MDMX and/or MDM2. MDM2 is a ubiquitin ligase whose activity results in ubiquitin- and proteasome-dependent p53 degradation, while MDMX inhibits p53-activated transcription by shielding the p53 transactivation domain. Interestingly, the oncogenic functions of MDMX appear to be more wide-spread than inhibition of p53. The present study aimed to elucidate the MDMX-controlled transcriptome. Therefore, we depleted MDMX with four distinct shRNAs from a high MDMX expressing uveal melanoma cell line and determined the effect on the transcriptome by RNAseq. Biological function analyses indicate the inhibition of the cell cycle regulatory genes and stimulation of cell death activating genes upon MDMX depletion. Although the inhibition of p53 activity clearly contributes to the transcription regulation controlled by MDMX, it appeared that the transcriptional regulation of multiple genes did not only rely on p53 expression. Analysis of gene regulatory networks indicated a role for Forkhead box (FOX) transcription factors. Depletion of FOXO proteins partly prevented the transcriptional changes upon MDMX depletion. Furthermore, depletion of FOXO proteins relatively diminished the growth inhibition upon MDMX knockdown, although the knockdown of the FOXO transcription factors also reduces cell growth. In conclusion, the p53-independent oncogenic functions of MDMX could be partially explained by its regulation of FOXO activity.

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Section: Resultsmentioning

confidence: 99%

MDMX Regulates Transcriptional Activity of p53 and FOXO Proteins to Stimulate Proliferation of Melanoma Cells

Heijkants

Teunisse

Jong

et al. 2022

Cancers

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“…genes. FAS has been reported to be regulated by p53 through a binding site located in its intron1 40 and both the p53 binding site and p53-mediated FAS regulation have been corroborated by high-throughput analyses 41 . The top tracks display p53 ChIP-seq data and the p53 response element (p53RE).…”

Section: Convergent Co-transcription From Super-promotersmentioning

confidence: 88%

“…We observed a strong positive correlation of daRNA and host RNA expression also in response to 3 h and 24 h E2 treatment (Figure 5F), suggesting a rather universal co-regulation of 5'-overlapping transcription through super-promoters. response element (p53RE) 41 as well as ATAC-seq, Pol II, H3K4me3, H3K27ac, H3K9ac, H3K4me1, and H3K36me3 data from ENCODE 45 . The bottom tracks display CAGE-seq-detected TSS (CTSS), RNA-seq, and QuantSeq-detected TTS (QTTS) counts on the +strand (PTP4A1) and the -strand (PTP4A1_daRNAs) from MCF-7 cells.…”

Section: Annotation Of Novel Downstream Antisense Transcripts Initiat...mentioning

confidence: 99%

“…Transcription factor binding data on p53, E2F4, and RFX7 are available through www.targetgenereg.org 41 . Epigenetic data are publicly available through ENCODE 45 : ATACseq (ENCFF782BVX), H2AFZ (ENCFF740HVA), H3K4me1 (ENCFF763NCP), H3K4me3 (ENCFF163MXP), H3K9ac (ENCFF327XJC), H3K27ac (ENCFF138YNG), H3K27me3 (ENCFF163QKN), H3K36me3 (ENCFF910BRP), H3K79me2 (ENCFF826OGB), H4K20me1 (ENCFF366GLZ), and Pol II (ENCFF827YIP).…”

Section: Data Availabilitymentioning

confidence: 99%

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Super-promoters: Cooperativity between juxtaposed promoters

Wiechens,

Vigliotti,

Riege

et al. 2023

Preprint

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The coordination of transcription through enhancers and promoters is a fundamental process that has a central role in development and disease 1–3. Convergent transcription, i.e., the collision of sense and antisense transcription, is ubiquitous in mammalian genomes 4–8 and believed to diminish RNA expression 9,10. Recently, antisense transcription downstream of promoters was found to be surprisingly prevalent 11–13. However, functional characteristics of promoters with convergent transcription are unknown. Here, we show that convergent transcription marks an unexpectedly cooperative promoter constellation we call super-promoters. By assessing transcriptional dynamic systems, we identified strongly cooperative constituent promoters that are connected through a distinct chromatin structure. Within these super-promoter constellations transcription factors can regulate both constituting promoters by binding to only one of them. Super-promoters comprise about a fourth of all active transcript starts and initiate 5’-overlapping antisense RNAs, an RNA class previously believed to be rare 4. Visualization of nascent RNA molecules provides evidence for convergent co-transcription at these loci. Our results demonstrate that super-promoters substantially expand the cis-regulatory repertoire and reveal limitations of the standing model of transcription interference. Together, our study revises the promoter architecture of many genes and calls for adjusting the promoter concept.

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“…The mass spectrometry proteomics data are available through the ProteomeXchange Consortium via the Proteomics Identifications Database (PRIDE) partner repository [71] with the dataset identifier PXD024869. ChIP-seq track hubs are available through www.TargetGeneReg.org [72]…”

Section: Data Availabilitymentioning

confidence: 99%

Multi-omics analysis identifies RFX7 targets involved in tumor suppression and neuronal processes

et al. 2023

Self Cite

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Recurrently mutated in lymphoid neoplasms, the transcription factor RFX7 is emerging as a tumor suppressor. Previous reports suggested that RFX7 may also have a role in neurological and metabolic disorders. We recently reported that RFX7 responds to p53 signaling and cellular stress. Furthermore, we found RFX7 target genes to be dysregulated in numerous cancer types also beyond the hematological system. However, our understanding of RFX7’s target gene network and its role in health and disease remains limited. Here, we generated RFX7 knock-out cells and employed a multi-omics approach integrating transcriptome, cistrome, and proteome data to obtain a more comprehensive picture of RFX7 targets. We identify novel target genes linked to RFX7’s tumor suppressor function and underscoring its potential role in neurological disorders. Importantly, our data reveal RFX7 as a mechanistic link that enables the activation of these genes in response to p53 signaling.

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TargetGeneReg 2.0: a comprehensive web-atlas for p53, p63, and cell cycle-dependent gene regulation

Cited by 35 publications

References 67 publications

MDMX Regulates Transcriptional Activity of p53 and FOXO Proteins to Stimulate Proliferation of Melanoma Cells

MDMX Regulates Transcriptional Activity of p53 and FOXO Proteins to Stimulate Proliferation of Melanoma Cells

Super-promoters: Cooperativity between juxtaposed promoters

Multi-omics analysis identifies RFX7 targets involved in tumor suppression and neuronal processes

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