Modulation of RUNX1-BRD4 cooperation by post-translational modification of a histone-like motif in the Runt domain
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA699602 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13633849.fastq.gz | Fastqsanger.gz | |||
| SRR13633850.fastq.gz | Fastqsanger.gz | |||
| SRR13633851.fastq.gz | Fastqsanger.gz | |||
| SRR13633852.fastq.gz | Fastqsanger.gz | |||
| SRR13633853.fastq.gz | Fastqsanger.gz |
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Project description:The RUNX1 transcription factor is strongly influenced by post-translational modifications. Here, we investigate a post-translational modification hotspot within a short peptide region in the evolutionarily conserved DNA-binding Runt domain. Cancer-specific mutations have been found clustered in this region, which also partially resembled the N-terminal tail of histone H4. We found that lysine acetylation of this histone-like motif promoted RUNX1 interaction with the BET-domain transcription co-activator BRD4,resulting in enhanced RUNX1 phosphorylation and transcriptional activity. Flanking post-translational modifications, such as arginine methylation and threonine phosphorylation, strongly inhibited the RUNX1-BRD4 complex formation. RNA sequencing revealed that knockdown of RUNX1 and BRD4 resulted in downregulation of genes associated with cell proliferation, suggesting that RUNX1 and BRD4 cooperated in driving cell cycle progression in gastric cancer. We identified AMIGO2 – known for its roles in invasion, proliferation and survival in cancer – as a common transcriptional target of RUNX1 and BRD4. Depletion of RUNX1 and BRD4 impaired cell proliferation and invasion in gastric cancer cells. Our work therefore indicates an oncogenic function for RUNX1-BRD4 interaction. Post-translational modification is reversible and can be pharmacologically targeted. We provide a basis for future design of drugs to specifically target the RUNX1-BRD4 interaction.
2025-01-31 | GSE166217 | GEO
Project description:ETV6-RUNX1 is a first-hit mutation in childhood B cell precursor acute lymphoblastic leukaemia. ETV6-RUNX1 is a fusion protein which inherits the DNA-binding runt domain from RUNX1. Here we performed chromatin precipitation for native RUNX1 and ETV6-RUNX1 using RUNX1 antibodies and specifically for the ETV6-RUNX1 fusion using a V5-tag pull down.
2022-10-31 | E-MTAB-12208 | biostudies-arrayexpress
Project description:Runt-related transcription factor 1 (RUNX1) is oncogenic in diverse types of leukemia and epithelial cancers where its expression is associated with poor prognosis. Current models suggest that RUNX1 cooperates with other oncogenic factors (e.g., NOTCH1, TAL1) to drive the expression of proto-oncogenes in T cell acute lymphoblastic leukemia (T-ALL) but the molecular mechanisms controlled by RUNX1 and its cooperation with other factors remain unclear. Integrative chromatin and transcriptional analysis following inhibition of RUNX1 and NOTCH1 revealed a surprisingly widespread role of RUNX1 in the establishment of global H3K27ac levels and that RUNX1 is required by NOTCH1 for cooperative transcription activation of key NOTCH1 target genes including MYC, DTX1, HES4, IL7R, and NOTCH3. Super-enhancers were preferentially sensitive to RUNX1 knockdown and RUNX1-dependent super-enhancers were disrupted following the treatment of a pan-BET inhibitor, I-BET151.
2023-03-26 | GSE99704 | GEO
Project description:Runt-related transcription factor 1 (RUNX1) is oncogenic in diverse types of leukemia and epithelial cancers where its expression is associated with poor prognosis. Current models suggest that RUNX1 cooperates with other oncogenic factors (e.g., NOTCH1, TAL1) to drive the expression of proto-oncogenes in T cell acute lymphoblastic leukemia (T-ALL) but the molecular mechanisms controlled by RUNX1 and its cooperation with other factors remain unclear. Integrative chromatin and transcriptional analysis following inhibition of RUNX1 and NOTCH1 revealed a surprisingly widespread role of RUNX1 in the establishment of global H3K27ac levels and that RUNX1 is required by NOTCH1 for cooperative transcription activation of key NOTCH1 target genes including MYC, DTX1, HES4, IL7R, and NOTCH3. Super-enhancers were preferentially sensitive to RUNX1 knockdown and RUNX1-dependent super-enhancers were disrupted following the treatment of a pan-BET inhibitor, I-BET151.
2023-03-26 | GSE99705 | GEO
Project description:Runt-related transcription factor 1 (RUNX1) is oncogenic in diverse types of leukemia and epithelial cancers where its expression is associated with poor prognosis. Current models suggest that RUNX1 cooperates with other oncogenic factors (e.g., NOTCH1, TAL1) to drive the expression of proto-oncogenes in T cell acute lymphoblastic leukemia (T-ALL) but the molecular mechanisms controlled by RUNX1 and its cooperation with other factors remain unclear. Integrative chromatin and transcriptional analysis following inhibition of RUNX1 and NOTCH1 revealed a surprisingly widespread role of RUNX1 in the establishment of global H3K27ac levels and that RUNX1 is required by NOTCH1 for cooperative transcription activation of key NOTCH1 target genes including MYC, DTX1, HES4, IL7R, and NOTCH3. Super-enhancers were preferentially sensitive to RUNX1 knockdown and RUNX1-dependent super-enhancers were disrupted following the treatment of a pan-BET inhibitor, I-BET151.
2023-03-25 | GSE99706 | GEO
Project description:ETV6-RUNX1 is a fusion protein bringing together almost the entire coding sequence of RUNX1, including the DNA binding runt domain, and the N-terminus of ETV6 which is known to include transcriptional repressors including histone deacetylation 3 (HDAC3). Here we perform ChIP-seq for the active chromatin mark H3K27ac in the NALM6 B-cell acute lymphoblastic leukaemia cell line expressing ETV6-RUNX1 or mutant derivatives of ETV6-RUNX1: Delta helix-loop-helix (dHLH) is a deletion of the pointed domain; R139G is a point mutation in the runt DNA-binding domain.
2022-10-31 | E-MTAB-12207 | biostudies-arrayexpress
Project description:BACKGROUND: Our previous studies showed that RUNX1 and ASXL1 mutations were frequently co-existed in chronic myelomonocytic leukemia (CMML) and clonal evolution of RUNX1 and/or ASXL1 occurred most frequently in chronic myeloid leukemia (CML) with myeloid blastic crisis. The molecular pathogenesis of cooperation of RUNX1 and ASXL1 mutations has not been reported yet. METHODS: Lentiviral-mediated stable transduction of RUNX1-WT/MT (R135T) in K562 cells which harboring ASXL1-MT (Y591X). RNA was extracted from stable cell line and used for gene-expression microarray analysis. RESULTS: For in vitro study, we overexpressed RUNX1-WT/MT (R135T) in K562 cells which harboring ASXL1-MT (Y591X). We found that RUNX1-MT augmented cell proliferation, colony formation, HOXA gene expression and inhibited megakaryocytic differentiation in ASXL1-MT K562 cells compared to RUNX1-WT or empty vector control. We performed gene expression profile of K562 cells overexpressed with EV, RUNX1-WT and RUNX1-R135T mutation. Gene expression microarray data revealed that 147 genes upregulated more than 2-fold in RUNX1-R135T expressing K562 cells compared to EV control cells. From gene expression data analysis, we found that inhibitor of DNA binding 1 (ID1), a key transcriptional regulator of hematopoietic stem cell (HSC) lineage commitment, is upregulated in RUNX1-R135T-transduced K562 cells compared to EV and RUNX1-WT-expressing cells.
2018-06-01 | GSE99640 | GEO
Project description:RUNX1 and ETV6-RUNX1 possess the same DNA-binding runt domain and are therefore expected to bind to canonical RUNX motifs. As the ETV6-RUNX1 fusion arises in the context of native RUNX1 expression, and since RUNX1 is retained or amplified in B-ALL, the two proteins are likely to compete for the same target sites. To assess this, we performed RUNX1 ChIP-seq in the presence of exogenous ETV6-RUNX1 (or non DNA binding ETV6-RUNX1-R139G) and the reciprocal experiment: ETV6-RUNX1 ChIP (using a V5 tag) in the presence of exogenous RUNX1 or vector control.
2022-10-31 | E-MTAB-12209 | biostudies-arrayexpress
Project description:Runt-related transcription factor 1 (RUNX1) plays critical roles in hematopoiesis including myeloid development. Runx1 binds Runt consensus motifs at promoters and regulatory elements of its target genes. Interestingly, several Runx1-binding RNA aptamers have been successfully developed. Additionally, mounting evidences suggest that transcription factors are capable of binding to RNAs. In this study, we performed a transcriptome-wide screen for Runx1-interacting RNAs in living cells using fRIP-Seq. Anti-Runx1 antibody was used to capture Runx1 in the monocytic cell line THP-1. RNAs co-immunoprecipitated with Runx1 were sequenced by paired-end massively parallel sequencing and analyzed by HOMER peak calling and annotation algorithms. By doing so, we identified a repertoire of RNAs interacting with Runx1. We further investigate functional role of these interactions in Runx1-mediated transcription regulation.
2021-10-27 | GSE140459 | GEO
Project description:Cellular binary fate decisions require the progeny to silence genes associated with the alternative fate. The major subsets of alpha:beta T cells have been extensively studied as a model system for fate decisions. While the transcription factor RUNX3 is required for the initiation of Cd4 silencing in CD8 T cell progenitors, it is not required to maintain the silencing of Cd4 and other helper T lineage genes. The other runt domain containing protein, RUNX1, silences Cd4 in an earlier T cell progenitor, but this silencing is reversed whereas the gene silencing after RUNX3 expression is not reverse. Therefore, we hypothesized that RUNX3 and not RUNX1 recruits other factors that maintains the silencing of helper T lineage genes in CD8 T cells. To this end, we performed a proteomics screen of RUNX1 and RUNX3 to determine candidate silencing factors.
2019-11-12 | PXD007511 | Pride