MKL1 augments megakaryocyte maturation by enhancing the SRF regulatory axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA445459 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6885310.fastq.gz | Fastqsanger.gz | |||
| SRR6885320.fastq.gz | Fastqsanger.gz | |||
| SRR6889500.fastq.gz | Fastqsanger.gz | |||
| SRR6885311.fastq.gz | Fastqsanger.gz | |||
| SRR6885321.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:SRF is a ubiquitous transcription factor that binds DNA in association with myocardin-family proteins (e.g. MKL1), or the ternary complex factor (TCF) family of ETS proteins. In primary hematopoietic cells, knockout of either SRF or MKL1 decreases megakaryocyte maturation caused thrombocytopenia, and MKL1 over-expression (MKL1OE) in the Human Erythroleukemia (HEL) cell line enhances megakaryopoiesis, but the mechanisms underlying these effects are unknown. To elucidate the role of SRF and MKL1 in megakaryopoiesis, integrated analysis was performed of anti-SRF ChIP-seq and RNA-seq data in undifferentiated and differentiated HEL cells, both with and without induction of MKL1OE. MKL1OE enhances TPA-induced megakaryopoiesis with 25% of genes upregulated, as opposed to 11% with TPA alone. MKL1OE increases SRF binding to genomic sites, and enhances expression of specific target cytoskeletal genes in response to TPA. Genes upregulated in response to TPA are predicted to be regulated by SRF and ETS factors, whereas those upregulated in TPA plus MKL1OE lack ETS binding motifs. Using ChIP-PCR, we validated that both SRF and MKL1 have increased binding at target upregulated genes, e.g. CORO1A, with MKL1OE. We show for the first time that MKL1 increases both the genomic association and activity of SRF, and upregulates genes that enhance megakaryopoiesis.
2018-10-29 | GSE112277 | GEO
Project description:SRF is a ubiquitous transcription factor that binds DNA in association with myocardin-family proteins (e.g. MKL1), or the ternary complex factor (TCF) family of ETS proteins. In primary hematopoietic cells, knockout of either SRF or MKL1 decreases megakaryocyte maturation caused thrombocytopenia, and MKL1 over-expression (MKL1OE) in the Human Erythroleukemia (HEL) cell line enhances megakaryopoiesis, but the mechanisms underlying these effects are unknown. To elucidate the role of SRF and MKL1 in megakaryopoiesis, integrated analysis was performed of anti-SRF ChIP-seq and RNA-seq data in undifferentiated and differentiated HEL cells, both with and without induction of MKL1OE. MKL1OE enhances TPA-induced megakaryopoiesis with 25% of genes upregulated, as opposed to 11% with TPA alone. MKL1OE increases SRF binding to genomic sites, and enhances expression of specific target cytoskeletal genes in response to TPA. Genes upregulated in response to TPA are predicted to be regulated by SRF and ETS factors, whereas those upregulated in TPA plus MKL1OE lack ETS binding motifs. Using ChIP-PCR, we validated that both SRF and MKL1 have increased binding at target upregulated genes, e.g. CORO1A, with MKL1OE. We show for the first time that MKL1 increases both the genomic association and activity of SRF, and upregulates genes that enhance megakaryopoiesis.
2018-10-29 | GSE112265 | GEO
Project description:MKL1 augments megakaryocyte maturation by enhancing the SRF regulatory axis [ChIP-seq]
| PRJNA445433 | ENA
Project description:MKL1 augments megakaryocyte maturation by enhancing the SRF regulatory axis [RNA-seq]
| PRJNA445458 | ENA
Project description:Megakaryoblastic Leukemia 1 (MKL1) was identified as part of the t(1;22) translocation specific to acute megakaryoblastic leukemia, but nothing is known regarding its role in hematopoiesis. Here we show that overexpression of MKL1 enhances megakaryocytic differentiation of the Human Erythroleukemia cell line (HEL). Microarray analysis reveals that MKL1 promotes expression of megakaryocyte-specific genes such as glycoprotein V (GP5), as well as cytoskeletal and adhesion molecule genes relevant to megakaryocyte differentiation and proplatelet formation. MKL1 is a transcriptional coactivator of Serum Response Factor. In this study, MKL1 also upregulates known SRF targets. Results provide insight into the role of MKL1 in megakaryocytopoiesis.
2008-12-10 | GSE13710 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-10-29 | GSE112279 | GEO
Project description:To test whether activity of the mechano-sensitive transcription factor complex, MKL1/SRF, can be exploited to reduce breast cancer metastasis
2023-01-01 | GSE215150 | GEO
Project description:Srf is a MADS-box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. In order to test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to SrfF/F mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/SrfF/F (KO) mice are born with normal mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased numbers and percentages of CD41+ megakaryocytes (WT: 0.41+/-0.06%; KO: 1.92+/-0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by both FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are downregulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production, due at least in part, to regulation of cytoskeletal genes. C-kit+CD41+ megakaryocyte progenitors from PF4-Cre/SRF C57BL/6 SRF WT (3) and C57BL/6 SRF KO (3) mice were sorted by flow cytometry and cultured for three days in thrombopoietin.
2010-07-13 | E-GEOD-21859 | biostudies-arrayexpress
Project description:Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds DNA at CArG (CC[A/T]6GG) domains in association with myocardin-family proteins (eg, myocardin-related transcription factor A [MRTFA]) or the ternary complex factor family of E26 transformation-specific (ETS) proteins. In primary hematopoietic cells, knockout of either SRF or MRTFA decreases megakaryocyte (Mk) maturation causing thrombocytopenia. The human erythroleukemia (HEL) cell line mimics the effects of MRTFA on Mk maturation, and MRTFA overexpression (MRTFAOE) in HEL cells enhances megakaryopoiesis. To identify the mechanisms underlying these effects, we performed integrated analyses of anti-SRF chromatin immunoprecipitation (ChIP) and RNA-sequencing data from noninduced and phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA])-induced HEL cells, with and without MRTFAOE We found that 11% of genes were upregulated with TPA induction, which was enhanced by MRTFAOE, resulting in an upregulation of 25% of genes. MRTFAOE increased binding of SRF to genomic sites and enhanced TPA-induced expression of SRF target genes. The TPA-induced genes are predicted to be regulated by SRF and ETS factors, whereas those upregulated by TPA plus MRTFAOE lack ETS binding motifs, and MRTFAOE skews SRF binding to genomic regions with CArG sites in regions relatively lacking in ETS binding motifs. Finally, ChIP-polymerase chain reaction using HEL cells and primary human CD34+ cell-derived subpopulations confirms that both SRF and MRTFA have increased binding during megakaryopoiesis at upregulated target genes (eg, CORO1A). We show for the first time that MRTFA increases both the genomic association and activity of SRF and upregulates genes that enhance primary human megakaryopoiesis.
| S-EPMC6199649 | biostudies-literature
Project description:We identified two isoforms of human MKL1 that differ in their N-terminal domains. Since MKL1 is a transcriptional coactivator of SRF and regulates many SRF target genes, we wanted to analyze if transcription is differentially regulated by the two isoforms upon stimulation of the Rho-actin-MKL1-SRF pathway.
2015-05-14 | GSE47209 | GEO