Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance

Jin, Wanzhu; Goldfine, Allison B.; Boes, Tanner; Henry, Robert R.; Ciaraldi, Theodore P.; Kim, Eun Young; Emecan, Merve; Fitzpatrick, Connor; Sen, Anish; Shah, Ankit; Mun, Edward C.; Vokes, Martha S.; Schroeder, Joshua; Tatro, Elizabeth; Jimenez-Chillaron, Jose; Patti, Mary‐Elizabeth

doi:10.1172/jci41940

Cited by 96 publications

(95 citation statements)

References 58 publications

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“…on May 7, 2018. by guest www.bloodjournal.org From small-molecule inhibitor of MKL1 that prevents MKL1 nuclear localization, 19 similarly reduced TPA-induced SM22-luc activation ( Figure 4B). Analysis of expression of endogenous SM22 by quantitative PCR revealed a TPA-induced increase within 6 hours.…”

Section: Mkl1 Nuclear Localization In Hel Cells Results In Activationmentioning

confidence: 86%

Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation

Smith

Teixeira

Chen³

et al. 2013

Blood

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• RhoA-induced actin polymerization promotes nuclear accumulation of MKL1 and transcriptional activation.• Thrombopoietin activates nuclear accumulation of MKL1 and transcriptional activation in primary megakarocytes.How components of the cytoskeleton regulate complex cellular responses is fundamental to understanding cellular function. Megakaryoblast leukemia 1 (MKL1), an activator of serum response factor (SRF) transcriptional activity, promotes muscle, neuron, and megakaryocyte differentiation. In muscle cells, where MKL1 subcellular localization is one mechanism by which cells control SRF activity, MKL1 translocation from the cytoplasm to the nucleus in response to actin polymerization is critical for its function as a transcriptional regulator. MKL1 localization is cell-type specific; it is predominantly cytoplasmic in unstimulated fibroblasts and some muscle cell types and is constitutively nuclear in neuronal cells. In the present study, we report that in megakaryocytes, subcellular localization and regulation of MKL1 is dependent on RhoA activity and actin organization. Induction of megakaryocytic differentiation of human erythroleukemia cells by 12-O-tetradecanoylphorbol-13-acetate and primary megakaryocytes by thrombopoietin promotes MKL1 nuclear localization. This MKL1 localization is blocked by drugs inhibiting RhoA activity or actin polymerization. We also show that nuclear-localized MKL1 activates the transcription of SRF target genes. This report broadens our knowledge of the molecular mechanisms regulating megakaryocyte differentiation. (Blood. 2013;121(7):1094-1101) IntroductionAlthough megakaryoblastic leukemia 1 (MKL1, also known as MRTF-A, MAL, or BSAC) plays a role in normal megakaryocytopoiesis, 1-3 much of what is known about this transcriptional coactivator of serum response factor (SRF) has been defined in fibroblasts and muscle cells. MKL1 promotes musclespecific gene expression, maintains mammary myoepithelial cell differentiation, and contributes to myocardial infarction-induced fibrosis and myofibroblast activation. [4][5][6][7] Other members of the MKL1 family include MKL2 and Myocardin. All 3 genes have been implicated in muscle cell differentiation, but have different patterns of cellular and developmental expression, which likely explains some of the differences in their knockout (KO) phenotypes. Although Mkl2-and Myocardin-KO mice are embryonic lethal with severe cardiac abnormalities, Mkl1-KO mice are viable with a less severe phenotype. Female Mkl1-KO mice have premature mammary gland involution that prevents lactation. 6,8 In addition, Mkl1-KO mice have impaired megakaryocytopoiesis defined by increased numbers of megakaryocytes in the BM, decreased ploidy of BM megakaryocytes, and low peripheral blood platelet counts. 1,3 In fibroblast cell lines, MKL1 activity is regulated posttranslationally by its subcellular localization, which is dependent on the actin cytoskeleton. 9-11 When MKL1 is bound to monomeric (G)-actin via its N-terminal RPEL domains, it is predominantly local...

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Section: Mkl1 Nuclear Localization In Hel Cells Results In Activationmentioning

confidence: 86%

Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation

Smith

Teixeira

Chen³

et al. 2013

Blood

View full text Add to dashboard Cite

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“…The small molecule CCG-1423 has been previously shown to block SRF/RhoA signaling by reducing nuclear MRTF-A levels and, as a result, preventing SRF from interacting with MRTF-A. 29 We tested SRF signaling inhibition using different concentrations of CCG-1423 in MB, and we noticed a strong reduction in overall expression levels of endogenous miR199a-5p transcripts (Figure 3a). Furthermore, shRNAi inhibition of SRF in both MB and MT resulted in a decrease of miR-199a-5p expression when compared with shLuciferase and mock controls (Figures 3b and c).…”

Section: Resultsmentioning

confidence: 88%

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

et al. 2013

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In patients with Duchenne muscular dystrophy (DMD), the absence of a functional dystrophin protein results in sarcolemmal instability, abnormal calcium signaling, cardiomyopathy, and skeletal muscle degeneration. Using the dystrophin-deficient sapje zebrafish model, we have identified microRNAs (miRNAs) that, in comparison to our previous findings in human DMD muscle biopsies, are uniquely dysregulated in dystrophic muscle across vertebrate species. MiR-199a-5p is dysregulated in dystrophindeficient zebrafish, mdx 5cv mice, and human muscle biopsies. MiR-199a-5p mature miRNA sequences are transcribed from stem loop precursor miRNAs that are found within the introns of the dynamin-2 and dynamin-3 loci. The miR-199a-2 stem loop precursor transcript that gives rise to the miR-199a-5p mature transcript was found to be elevated in human dystrophic muscle. The levels of expression of miR-199a-5p are regulated in a serum response factor (SRF)-dependent manner along with myocardin-related transcription factors. Inhibition of SRF-signaling reduces miR-199a-5p transcript levels during myogenic differentiation. Manipulation of miR-199a-5p expression in human primary myoblasts and myotubes resulted in dramatic changes in cellular size, proliferation, and differentiation. MiR-199a-5p targets several myogenic cell proliferation and differentiation regulatory factors within the WNT signaling pathway, including FZD4, JAG1, and WNT2. Overexpression of miR-199a-5p in the muscles of transgenic zebrafish resulted in abnormal myofiber disruption and sarcolemmal membrane detachment, pericardial edema, and lethality. Together, these studies identify miR-199a-5p as a potential regulator of myogenesis through suppression of WNT-signaling factors that act to balance myogenic cell proliferation and differentiation.

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“…While, to our knowledge, this association has not yet been experimentally verified, a recent paper shows that insulin resistance in humans and mice is marked by increased SRF activity ( Jin et al 2011). Similarly, GREAT analysis implicates GABPA in regulating ''general transcription by RNA polymerase I'' (P < 10 À11 ; 19 binding sites at FDR = 13%), an enzyme that transcribes ribosomal RNA.…”

Section: à25mentioning

confidence: 97%

PRISM offers a comprehensive genomic approach to transcription factor function prediction

et al. 2013

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The human genome encodes 1500-2000 different transcription factors (TFs). ChIP-seq is revealing the global binding profiles of a fraction of TFs in a fraction of their biological contexts. These data show that the majority of TFs bind directly next to a large number of context-relevant target genes, that most binding is distal, and that binding is context specific. Because of the effort and cost involved, ChIP-seq is seldom used in search of novel TF function. Such exploration is instead done using expression perturbation and genetic screens. Here we propose a comprehensive computational framework for transcription factor function prediction. We curate 332 high-quality nonredundant TF binding motifs that represent all major DNA binding domains, and improve cross-species conserved binding site prediction to obtain 3.3 million conserved, mostly distal, binding site predictions. We combine these with 2.4 million facts about all human and mouse gene functions, in a novel statistical framework, in search of enrichments of particular motifs next to groups of target genes of particular functions. Rigorous parameter tuning and a harsh null are used to minimize false positives. Our novel PRISM (predicting regulatory information from single motifs) approach obtains 2543 TF function predictions in a large variety of contexts, at a false discovery rate of 16%. The predictions are highly enriched for validated TF roles, and 45 of 67 (67%) tested binding site regions in five different contexts act as enhancers in functionally matched cells.

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Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance

Cited by 96 publications

References 58 publications

Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation

Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

PRISM offers a comprehensive genomic approach to transcription factor function prediction

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