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Relieving Dyrk1a repression of MKL1 corrects developmental defects in infantile megakaryocytes

ABSTRACT: Adult and fetal megakaryocytes are morphologically different. These differences contribute to neonatal thrombocytopenia in premature neonates and in neonates after infection and also contribute to poor megakaryocytes engrafment after umbilical cord blood transplant. We found that Dyrk1a kinase inhibition shift the fetal megakaryocytes phenotype toward adult phenotype. This effect is mediated by MKL1 the master regulator of megakaryocytes morphogenesis. To identify deferences between adult and fetal megakaryocytes we performed RNA seq of adult derived megakaryocytes and fetal derived megakaryocytes treated and untreated with Dyrk inhibitors. Through this approach we identified cohorts of genes co-regulated in adult megakaryocytes and fetal megakaryoctes treated with the dyrk inhibitors. More importantly, we found that the dyrk inhibition in fetal megakaryocytes leads to upregulation of a significant number of MKL1 target genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE195671 | GEO | 2022/08/30

REPOSITORIES: GEO

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Relieving Dyrk1a repression of MKL1 corrects developmental defects in infantile megakaryocytes

Project description:Adult and fetal megakaryocytes are morphologically different. These differences contribute to neonatal thrombocytopenia in premature neonates and in neonates after infection and also contribute to poor megakaryocytes engraftment after umbilical cord blood transplant. We found that Dyrk1a kinase inhibition shift the fetal megakaryocytes phenotype toward adult phenotype. This effect is mediated by MKL1 the master regulator of megakaryocytes morphogenesis. To identify differences between adult and fetal megakaryocytes we performed RNA seq of adult derived megakaryocytes and fetal derived megakaryocytes treated and untreated with Dyrk inhibitors. Through this approach we identified cohorts of genes co-regulated in adult megakaryocytes and fetal megakaryocytes treated with the dyrk inhibitors. More importantly, we found that the dyrk inhibition in fetal megakaryocytes leads to upregulation of a significant number of MKL1 target genes.

2022-05-29 | GSE204909 | GEO

Relieving Dyrk1a repression of MKL1 corrects developmental defects in infantile megakaryocytes

Project description:Relieving Dyrk1a repression of MKL1 corrects developmental defects in infantile megakaryocytes

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RNAi knock-down of MKL1 in human megakaryocytes derived from cord blood or cytapheresis

Project description:Characterize the genes regulated by MKL1/SRF complex in human megakaryocytes (MKs) derived from cord blood or cytapheresis : Using a knock down approach by small interference of MKL1 in MK progenitors, we observed a decrease in the percentage of cells with actin polymerization after adhesion on various substrates, an increase of mean ploidy level and apoptosis. Furthermore, MKL1 inhibition induced a major defect in pro-platelet formation and MKs migration. These results clearly demonstrate that MKL1 is involved in the cytoskeleton organization and maturation of MKs as well as in platelet formation. The goal of gene profiling was to identify new potential MKL1/SRF targets the expression level of which was down regulated after MKL1 inhibition: Human CD34+ cells isolated from cord blood or cytapheresis were transduced by a control lentivirus (designed as SCR; scramble) or by the lentivirus encoding for shRNA of MKL1 (designed as shMKL1) both containing a GFP expressed under the control of PGK promoter. The cells were than grown in serum free medium supplemented by thrombopoietin leading to a generation of megakaryocytes. At day 9 of culture (80% of MKs), the GFP positive cells were sorted, RNAs were extracted and submitted to hybridization as described in annex protocols. Two lists of genes (one for cord blood samples and one for cytapheresis samples) deregulated after the repression of MKL1 were done comparing the intensity of hybridization between SCR and shMKL1 samples. The common list of genes deregulated in MKs from cord blood and cytapheresis after the repression of MKL1 was than generated.

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MKL1-dependent tenascin-C transcription

Project description:The aim of the experiment is to investigate whether megakaryoblastic leukemia factor-1 (MKL1) induces tenascin-C in normal mammary epithelial HC11 and tumor mammary epithelial 4T1 cell lines, as well as to identify other genes that are transcriptionally regulated by MKL1. For this purpose, we compared the transcriptomes of HC11 and 4T1 cell lines stably expressing the full length (FL) MKL1 protein (HC11-FL and 4T1-FL cell lines) to respective control cell lines stably transfected with an empty vector (HC11-control and 4T1-control cell lines).

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MKL1 promotes megakaryocytic differentiation in HEL cells

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.

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Identification of megakaryoblastic leukemia-1 (Mkl1) target genes in 4T1 mammary carcinoma cells

Project description:The present study was designed to identify Mkl1 target genes whose expression requires either the B1 site of Mkl1 and serum response factor (SRF), respectively, or the SAP domain of Mkl1. For this purpose, we obtained the transcriptomes of four stable 4T1 cell lines that either overexpress full length Mkl1-RFP (4T1-FL), Mkl1-RFP with a mutated SRF-interaction site (4T1-mutB1), Mkl1-RFP with a deletion of the SAP domain (4T1-ΔSAP) or an empty vector encoding RFP alone (4T1 control).

2016-07-15 | GSE59459 | GEO

MKL1 ChIP-seq in sham and hepatectomy mouse liver.

Project description:To investigate the function of MKL1 in liver regeneration. Wild-type C57/B6 mouse were performed sham operation or two-thirds hepatectomy. 24 hours later, ChIP-seq was did with MKL1 antibody.

2024-01-01 | GSE222055 | GEO

Differential regulation of gene expression by two isoforms of the human transcriptional coactivator MKL1

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. Activity of the Rho-actin-MKL1 pathway was induced in EcR293 cell lines stably over-expressing the empty vector control, a 5’UTR-full length MKL1_S construct, or a 5’UTR-full length MKL1_L construct by LPA treatment.

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