Runx1-deficiency induced changes in transcription and chromatin accessibility in mK4 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE158093 | GEO | 2021/06/07
REPOSITORIES: GEO
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Project description:Runx1-deficiency induced changes in transcription and chromatin accessibility in mK4 cells
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Project description:The conserved Runt-related (RUNX) transcription factor family are well-known master regulators of developmental and regenerative processes. Both Runx1 and Runx2 are expressed in satellite cells (SC) and skeletal myotubes. Conditional deletion of Runx1 in adult SC negatively impacted self-renewal, and skeletal muscle maintenance was impaired; Runx1-deficient SC cannot support muscle regeneration in response to injury. To determine the unique molecular functions of Runx1 that cannot be compensated by Runx2 we deleted Runx1 in C2C12 that retain Runx2 expression and established that myoblasts differentiation was blocked in vitro due in part to ectopic expression of Mef2c, a target repressed by Runx1. Structure-function analysis demonstrated that the Ets-interacting MID/EID region of Runx1 absent from Runx2 is critical to regulating myoblasts proliferation, differentiation, and fusion. Analysis of in-house and published ChIP-seq datasets from Runx1 (T-cells, muscle) versus Runx2 (preosteoblasts) dependent tissue identified enrichment for a Ets:Runx composite site in Runx1-dependent tissues. Comparing ATACseq datasets from WT and Runx1KO C2C12 cells showed that the Ets:Runx composite motif was enriched in peaks open exclusively in WT cells compared to peaks unique to Runx1KO cells. Thus, engagement of a set of targets by the RUNX1/ETS complex define the non-redundant functions of Runx1
2023-11-17 | GSE248045 | GEO
Project description:The conserved Runt-related (RUNX) transcription factor family are well-known master regulators of developmental and regenerative processes. Both Runx1 and Runx2 are expressed in satellite cells (SC) and skeletal myotubes. Conditional deletion of Runx1 in adult SC negatively impacted self-renewal, and skeletal muscle maintenance was impaired; Runx1-deficient SC cannot support muscle regeneration in response to injury. To determine the unique molecular functions of Runx1 that cannot be compensated by Runx2 we deleted Runx1 in C2C12 that retain Runx2 expression and established that myoblasts differentiation was blocked in vitro due in part to ectopic expression of Mef2c, a target repressed by Runx1. Structure-function analysis demonstrated that the Ets-interacting MID/EID region of Runx1 absent from Runx2 is critical to regulating myoblasts proliferation, differentiation, and fusion. Analysis of in-house and published ChIP-seq datasets from Runx1 (T-cells, muscle) versus Runx2 (preosteoblasts) dependent tissue identified enrichment for a Ets:Runx composite site in Runx1-dependent tissues. Comparing ATACseq datasets from WT and Runx1KO C2C12 cells showed that the Ets:Runx composite motif was enriched in peaks open exclusively in WT cells compared to peaks unique to Runx1KO cells. Thus, engagement of a set of targets by the RUNX1/ETS complex define the non-redundant functions of Runx1
2023-11-17 | GSE248044 | GEO
Project description:Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes [ATAC-seq]
| PRJNA544085 | ENA
Project description:Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/β-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast−adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis. Using unbiased genome-wide RNA-seq data from Runx1f/fCol1α1-Cre, Runx1ffTwist2-cre, Runx1f/f;Col2α1-Cre and their control osteoblasts, we examined Runx1-mediated transcriptional targets that could account for osteoblast differentiation defects and increased adipocytes.
2022-09-26 | GSE213930 | GEO
Project description:Comparative analysis of RUNX1 and RUNX2 responsiveness in the presence or absence of E2
2016-02-01 | GSE65616 | GEO
Project description:Runx1 is expressed in regenrating muscle, specifically in the muscle adult stem cells- the satellite cells. Its exact role and target genes were yet to be identified. We report here the genome wide open chromatin paatern, as established by ATAC-seq Examination ofgenome wide pattern naked and therefore trhansposase accecible genomic DNA in primary myoblasts (PM)
2015-07-23 | E-GEOD-63573 | biostudies-arrayexpress
Project description:To identify the target genes of Runx1 in MLL fusion leukemia, we performed microarray analysis using control and Runx1-deficient MLL-ENL leukemia cells. Runx1 intact and excised bone marrow cells were transduced with MLL-ENL and transplanted into congenic mice. Leukemic cells were harvested from moribund mice, and gene expression was compared using 3 independent leukemia cells for each genotype.
2013-06-30 | E-GEOD-47402 | biostudies-arrayexpress
Project description:Causal mutations in multiple classes of genes have been identified in MDS patients with some patients harboring more than one mutation. Interestingly, double mutations tend to occur in different classes, rather than the same classes of genes, as exemplified by frequent co-occurring mutations in the transcription factor RUNX1 and the splicing factor SRSF2. Here we report a mouse model in which Runx1 knockout was combined with the Srsf2 P95H mutation to cause multi-lineage hematopoietic defects. Besides their additive and synergistic effects, we also unexpectedly noted a degree of antagonizing activity of single mutations in specific hematopoietic progenitors. To uncover the mechanism, we further developed a cellular model using human K562 cells and performed parallel gene expression and splicing analyses in both human and murine contexts. We performed RNA-seq on sorted Lineage- c-Kit+ (LK) hematopoietic progenitors from bone marrow of mice from WT, runx1 KO , Srsf2 P95H knock in and runx1 Srsf2 P95H double mutants. We also performed RNA-seq on set of isogenic K562 cell lines: wild type (WT), SRSF2 P95H knock-in (SRSF2P95H/+/+), RUNX1 knockdown (RUNX1 KD), and SRSF2 P95H knock-in with RUNX1 knockdown (Double). Strikingly, while RUNX1 deficiency was responsible for altered transcription in both single and double mutants, it also induced dramatic changes in global splicing, as seen with mutant SRSF2, and only their combination induced mis-splicing of genes selectively enriched in the DNA damage response and cell cycle checkpoint pathways. Collectively, these data reveal the convergent impact of a prototypic MDS-associated double mutant on RNA processing and suggest that aberrant DNA damage repair and cell cycle regulation critically contribute to MDS development.
2022-09-27 | GSE200446 | GEO
Project description:To identify the target genes of Runx1 in MLL fusion leukemia, we performed microarray analysis using control and Runx1-deficient MLL-ENL leukemia cells.
2013-06-30 | GSE47402 | GEO