Modulation of Smooth Muscle Gene Expression by Association of Histone Acetyltransferases and Deacetylases with Myocardin

Cao, Dongsun; Wang, Zhigao; Zhang, Chun Li; Oh, Jiyeon; Xing, Weibing; Li, Shijie; Richardson, James A.; Wang, Da Zhi; Olson, Eric N.

doi:10.1128/mcb.25.1.364-376.2005

Cited by 165 publications

(159 citation statements)

References 59 publications

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“…Myocd interacts with positive (p300) and negative (HDAC5) coregulators of chromatin remodeling to effect changes in SMC gene expression (18). Here we show that the HDAC5 interacting domain of Myocd (poly Q) is partly required for transrepression.…”

Section: Discussionmentioning

confidence: 78%

“…Further, antisense-HDAC5 rescues the suppression of Myog in cells stably transfected with Myocd. Interestingly, repression cannot be rescued with p300 (data not shown), which physically binds to the TAD of Myocd (18) and is a crucial coactivator of MyoD-dependent gene expression (22). This outcome implies that repression is not the result of Myocd binding limiting amounts of p300.…”

Section: Discussionmentioning

confidence: 90%

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Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation

Long

Creemers

Wang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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deacetylase ͉ myogenic ͉ SRF ͉ MEF2 ͉ promoter S keletal muscle identity is controlled primarily by four skeletal muscle-specific myogenic regulatory factors (MRFs), MyoD, myogenin (Myog), Myf5, and MRF4, which cooperate with the myocyte enhancer factor-2 (MEF2) transcription factor to activate skeletal muscle gene expression (1). Although the MRFs act in a dominant manner and can convert a variety of cell types, including smooth muscle, into skeletal muscle (2), there are settings in which skeletal muscle can be induced to transdifferentiate into other cell types, suggesting that the MRFs may be subordinate to other cell-specific transcription factors (3, 4).Much of the work related to transcriptional regulation of smooth muscle cell (SMC) differentiation has focused on serum response factor (SRF), a widely expressed transcription factor that binds the CArG box found in the regulatory regions of many SMC-specific genes (5). Genetic inactivation of SRF (6) and CArG mutagenesis studies in transgenic mice (7) have confirmed the necessity of CArG-SRF in controlling SMC differentiation. However, SRF is only a weak transcriptional activator and requires interacting cofactors that recruit proteins to promote a permissive state for gene transcription. One such cofactor is myocardin (Myocd), which is expressed primarily in cardiac and SMCs and displays high transcriptional activity (8). Myocd can activate SMC-specific genes (9), and genetic deletion of Myocd in mice leads to defective vascular SMC differentiation (10). Thus, Myocd displays features of a master regulator of the SMC phenotype.In an effort to define the cells of the cardiovascular system derived from Myocd-dependent lineages, we performed lineage tracing in mouse embryos by introducing Cre recombinase into the Myocd locus and monitoring the expression of a Credependent lacZ from the ROSA26 reporter (R26R) mouse line. Consistent with previous expression data, cardiac and vascular SMCs are derived from Myocd-dependent lineages. Surprisingly, skeletal muscle in these mice also expressed lacZ, indicating its derivation from a Myocd-dependent lineage. However, rather than functioning as an activator of skeletal muscle gene expression, Myocd represses MyoD-mediated stimulation of the Myog promoter and blocks skeletal muscle differentiation in vitro. At the same time, Myocd transactivates SMC contractile protein genes, thereby converting skeletal myoblasts to an SMC phenotype. These results suggest that Myocd acts as a bifunctional switch for muscle differentiation by concurrently opposing the gene program for skeletal muscle differentiation and specifying a SMC fate. Results Myocd Is Expressed in Progenitors of Skeletal Muscle.Myocd is expressed throughout the atrial and ventricular myocardium and in a subset of vascular and visceral SMCs (8). To trace the embryonic origins of Myocd-expressing lineages, we performed lineage tracing by creating a mouse in which the first exon of Myocd was replaced with a Cre-recombinase cassette [supporting information (SI) Fig. ...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 90%

Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation

Long

Creemers

Wang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Isoxazole enhanced the phosphorylation and nuclear export of histone deacetylase 5 (HDAC5) in neural stem cells, thereby promoting transcriptional activation of myocyte enhancer factor-2 target genes (29) and also stimulated p300 and cAMP response element binding protein acetyl-transferase activity in pancreatic β-cells (39). Of note, myocardin family proteins bind to and are stimulated by p300 and are repressed by HDAC activity (40).…”

Section: Discussionmentioning

confidence: 99%

Activation of MRTF-A–dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing

Velasquez

Sutherland²,

Liu³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Myofibroblasts are contractile smooth muscle-like cells that control tissue repair and remodeling. Inappropriate myofibroblast differentiation can cause organ fibrosis or inefficient wound healing. In this article, we demonstrate that myocardin-related transcription factor (MRTF)-A is necessary for myofibroblast differentiation. We also identify an isoxazole ring-containing small molecule that stimulates MRTF-A–dependent gene expression, myofibroblast differentiation, and wound healing. These findings suggest that targeting MRTFs pharmacologically may prove useful in treating fibrotic diseases.

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“…Furthermore, studies have shown that HDAC4 can be recruited to enhance the platelet-derived growth factor-BB-mediated repression of SM ␣-actin gene expression (30) through the activation of ERK1/2 (extracellular signal-regulated kinase 1/2) pathway (47). In addition, HDAC4 has been shown to interact with serum response factor (48) and its coactivator myocardin (49).…”

Section: Discussionmentioning

confidence: 99%

miR-10a Contributes to Retinoid Acid-induced Smooth Muscle Cell Differentiation

Huang

Xie

Sun

et al. 2010

Journal of Biological Chemistry

118

103

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MicroRNAs (miRs) have been reported to play a critical role in muscle differentiation and function. The purpose of this study is to determine the role of miRs during smooth muscle cell (SMC) differentiation from embryonic stem cells (ESCs). MicroRNA profiling showed that miR-10a expression is steadily increased during in vitro differentiation of mouse ESCs into SMCs. Lossof-function approaches using miR-10a inhibitors uncovered that miR-10a is a critical mediator for SMC lineage determination in our retinoic acid-induced ESC/SMC differentiation system. In addition, we have documented for the first time that histone deacetylase 4 is a novel target of miR-10a and mediates miR-10a function during ESC/SMC differentiation. To determine the molecular mechanism through which retinoic acid induced miR-10a expression, a consensus NF-B element was identified in the miR-10a gene promoter by bioinformatics analysis, and chromatin immunoprecipitation assay confirmed that NF-B could bind to this element. Finally, inhibition of NF-B nuclear translocation repressed miR-10a expression and decreased SMC differentiation from ESCs. Our data demonstrate for the first time that miR-10a is a novel regulator in SMC differentiation from ESCs. These studies suggest that miR-10a may play important roles in vascular biology and have implications for the diagnosis and treatment of vascular diseases.

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Modulation of Smooth Muscle Gene Expression by Association of Histone Acetyltransferases and Deacetylases with Myocardin

Cited by 165 publications

References 59 publications

Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation

Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation

Activation of MRTF-A–dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing

miR-10a Contributes to Retinoid Acid-induced Smooth Muscle Cell Differentiation

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