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Comparative transcriptome analysis of DFAT cells after the treatment with Y-27632 and the transfection of Mkl1 siRNA

ABSTRACT: Cellular differentiation is regulated through activation and repression of defined transcription factors. A hallmark of differentiation is a pronounced change in cell shape, which is determined by dynamics of the actin cytoskeleton. In de-differentiated fat (DFAT) cells and 3T3-L1 cells, we showed that treatment with the ROCK inhibitor Y-27632, by inducing remodeling of the actin cytoskelton, causes adipocyte differentiation. In addition, we found that depletion of MKL1, an actin binding transcriptional coactivator, elicits adipogenesis. To investigate whether regulation of MKL1 by actin cytoskeleton dynamics drives adipocyte differentiation, we compared the gene expression changes resulting from DFAT cells after treatment with Y-27632 and transfection of Mkl1 siRNA.

ORGANISM(S): Mus musculus

PROVIDER: GSE52334 | GEO | 2014/03/28

SECONDARY ACCESSION(S): PRJNA227434

REPOSITORIES: GEO

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Comparative transcriptome analysis of DFAT cells after the treatment with Y-27632 and the transfection of Mkl1 siRNA

Project description:Cellular differentiation is regulated through activation and repression of defined transcription factors. A hallmark of differentiation is a pronounced change in cell shape, which is determined by dynamics of the actin cytoskeleton. In de-differentiated fat (DFAT) cells and 3T3-L1 cells, we showed that treatment with the ROCK inhibitor Y-27632, by inducing remodeling of the actin cytoskelton, causes adipocyte differentiation. In addition, we found that depletion of MKL1, an actin binding transcriptional coactivator, elicits adipogenesis. To investigate whether regulation of MKL1 by actin cytoskeleton dynamics drives adipocyte differentiation, we compared the gene expression changes resulting from DFAT cells after treatment with Y-27632 and transfection of Mkl1 siRNA. Using Affymetrix mouse genome array, we compared global gene expression profiles in DFAT cells after treatment with Y-27632 and transfection with Mkl1 siRNA to search for particular biological functions in genes of which expression intensities were increased and decreased.

2014-03-28 | E-GEOD-52334 | biostudies-arrayexpress

Gene regulation in human epidermal keratinocytes by a Rho kinase inhibitor (Y-27632)

Project description:We previously demonstrated that the lifespan of primary human keratinocytes could be extended indefinitely by culture in the presence of the Rho kinase (ROCK) inhibitor Y-27632. Here, gene expression analysis of primary human epidermal keratinocytes cells grown in the presence of Y-27632 demonstrates that ROCK inhibition primarily inhibits keratinocyte differentiation.

2014-03-31 | GSE52515 | GEO

RNA-seq, ChIP-seq and ATAC-seq analysis of MKL1 blocked cells during reprogramming

Project description:Actins and regulators of actin dynamics generate contractile forces providing major mechanical and structural support for the cell. Whether and how they actively participate in cell fate control is not clear. Here, we report the actin responsive transcription factor complex MKL1/SRF, the major transcriptional regulator of large numbers of actin cytoskeletal genes, as an important regulator of genomic accessibility and cell fate outcome. Somatic cells with weaker MKL1/SRF activity progress toward pluripotency efficiently while sustained MKL1/SRF activity at a level seen in typical fibroblasts is sufficient to stall cells on their trajectory toward pluripotency. This altered cell fate outcome is associated with an overactive actin cytoskeleton, which connects to chromatin via the LINC complex, preventing its conversion into a relaxed, open conformation that allows sufficient accessibility to pluripotency-inducing transcription factors. Interfering with actin polymerization at appropriate times promotes pluripotency induction. Thus, we reveal a previously unappreciated aspect of cell fate control exerted by the actin based cytoskeletal system.

2019-03-01 | GSE120399 | GEO

MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization

Project description:Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics by co-activating serum response factor. Recently, the first human case with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with two siblings with a homozygous frameshift mutation in MKL1. The index case deceased as an infant from progressive and severe pneumonia by Pseudomonas aeruginosa and poor wound healing. The younger sib was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. Apart from the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as transcriptional co-regulator. Degranulation was enhanced upon suboptimal neutrophil activation, while production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent defect in phagocytosis and bacterial killing was found. Also monocyte-derived macrophages showed intact phagocytosis; lymphocyte counts and proliferative capacity were normal. Non-hematopoietic primary patient fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and filamentous actin (F-actin) content, most probably due to compensatory mechanisms of MKL2, which is not expressed in neutrophils. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as most prominent features.

2020-03-16 | GSE134644 | GEO

Irradiated feeder cells and Y-27632

Project description:Expression data from this experiment is part of a larger project aimed at defining the individual effects and synergistic effects of ROCK inhibitor Y-27632 and conditioned media from irradiated J2 cells when applied to epithelial cells. This data set consists of four individual samples, each of which are total RNA collected from human foreskin keratinocyte cells, either grown in F medium (control), treated with Y-27632, grown in conditioned medium (as described in associated publication), or both treatments.

2014-09-15 | GSE61226 | GEO

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.

2009-09-14 | E-TABM-640 | biostudies-arrayexpress

Expression data from Human Embrionic Stem Cells (hESC) from three different lines cultured on feeders or Matrigel with and without ROCK Inhibitor Y-27632

Project description:Microarray expression data from three different cell lines of human embrionic stem cells (Hs181, Hs293, Hs420), grown under feeder and feeder-free conditions (matrigel) with the addition of Y-27632 (ROCK Inhibitor) We assessed the difference between cell lines and the impact of feeder-free vs matrigel conditions upon the addition of the ROCK Inhibitor Y-27632

2018-01-01 | GSE102108 | 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.

2015-05-14 | E-GEOD-47209 | biostudies-arrayexpress

Twinfilin regulates breast cancer cell invasion and interleukin-11 expression through the miR-206/ MKL1/SRF pathway

Project description:Recent studies have implicated genes that control actin cytoskeleton dynamics as important regulators in cellular invasion, a critical step in metastasis. Many of their downstream pathways still remain to be discovered. MicroRNAs have emerged as important epigenetics regulators of important cellular processes and aid in the identification of pathways involved in breast cancer progression and metastasis. In this study, we characterized the miR-206 downstream pathway specifically its direct target, Twinfilin (TWF1), a g-actin regulator and their downstream target, interleukin-11 (IL-11). We determined that miR-206 and TWF1 regulate IL-11 expression through the mycocardian-related transcription factor (MRTF-A or MKL1) and serum response factor (SRF) complex. Identification of this novel pathway that regulates breast cancer invasion will aid in the understanding of metastasis and development of new treatment strategies.

2014-12-31 | GSE59751 | GEO

Twinfilin regulates breast cancer cell invasion and interleukin-11 expression through the miR-206/ MKL1/SRF pathway

2014-12-31 | GSE59751 | GEO

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