scholarly journals CREB-mediated transcriptional activation of NRMT1 drives muscle differentiation

Transcription ◽  
2021 ◽  
pp. 1-17
Author(s):  
John G. Tooley ◽  
James P. Catlin ◽  
Christine E. Schaner Tooley
Keyword(s):  
Transcriptional Activation ◽  
Muscle Differentiation

scholarly journals MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206

2006 ◽  
Vol 175 (1) ◽  
pp. 77-85 ◽  
Author(s):  
Miriam I. Rosenberg ◽  
Sara A. Georges ◽  
Amy Asawachaicharn ◽  
Erwin Analau ◽  
Stephen J. Tapscott
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Transcriptional Activation ◽  
Cell Types ◽  
Muscle Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Distinct Cell ◽  
Muscle Genes ◽  
Suppression Of Gene Expression ◽  
Dystrophin Protein

Terminal differentiation of distinct cell types requires the transcriptional activation of differentiation-specific genes and the suppression of genes associated with the precursor cell. For example, the expression of utrophin (Utrn) is suppressed during skeletal muscle differentiation, and it is replaced at the sarcolemma by the related dystrophin protein. The MyoD transcription factor directly activates the expression of a large number of skeletal muscle genes, but also suppresses the expression of many genes. To characterize a mechanism of MyoD-mediated suppression of gene expression, we investigated two genes that are suppressed in fibroblasts converted to skeletal muscle by MyoD, follistatin-like 1 (Fstl1) and Utrn. MyoD directly activates the expression of a muscle-specific microRNA (miRNA), miR-206, which targets sequences in the Fstl1 and Utrn RNA, and these sequences are sufficient to suppress gene expression in the presence of miR-206. These findings demonstrate that MyoD, in addition to activating muscle-specific genes, induces miRNAs that repress gene expression during skeletal muscle differentiation.

scholarly journals Permissive Roles of Phosphatidyl Inositol 3-Kinase and Akt in Skeletal Myocyte Maturation

2004 ◽  
Vol 15 (2) ◽  
pp. 497-505 ◽  
Author(s):  
Elizabeth M. Wilson ◽  
Jolana Tureckova ◽  
Peter Rotwein
Keyword(s):  
Growth Factors ◽  
Signaling Pathways ◽  
Transcriptional Activation ◽  
Muscle Development ◽  
Kinase Inhibitor ◽  
Troponin T ◽  
Phosphatidyl Inositol ◽  
Muscle Differentiation ◽  
Pi3 Kinase ◽  
Dominant Negative

Skeletal muscle differentiation, maturation, and regeneration are regulated by interactions between signaling pathways activated by hormones and growth factors, and intrinsic genetic programs controlled by myogenic transcription factors, including members of the MyoD and myocyte enhancer factor 2 (MEF2) families. Insulin-like growth factors (IGFs) play key roles in muscle development in the embryo, and in the maintenance and hypertrophy of mature muscle in the adult, but the precise signaling pathways responsible for these effects remain incompletely defined. To study mechanisms of IGF action in muscle, we have developed a mouse myoblast cell line termed C2BP5 that is dependent on activation of the IGF-I receptor and the phosphatidyl inositol 3-kinase (PI3-kinase)-Akt pathway for initiation of differentiation. Here, we show that differentiation of C2BP5 myoblasts could be induced in the absence of IGF action by recombinant adenoviruses expressing MyoD or myogenin, but it was reversibly impaired by the PI3-kinase inhibitor LY294002. Similar results were observed using a dominant-negative version of Akt, a key downstream component of PI3-kinase signaling, and also were seen in C3H 10T1/2 fibroblasts. Inhibition of PI3-kinase did not prevent accumulation of muscle differentiation-specific proteins (myogenin, troponin T, or myosin heavy chain), did not block transcriptional activation of E-box containing muscle reporter genes by MyoD or myogenin, and did not inhibit the expression or function of endogenous MEF2C or MEF2D. An adenovirus encoding active Akt could partially restore terminal differentiation of MyoD-expressing and LY294002-treated myoblasts, but the resultant myofibers contained fewer nuclei and were smaller and thinner than normal, indicating that another PI3-kinase-stimulated pathway in addition to Akt is required for full myocyte maturation. Our results support the idea that an IGF-regulated PI3-kinase pathway functions downstream of or in parallel with MyoD, myogenin, and MEF2 in muscle development to govern the late steps of differentiation that lead to multinucleated myotubes.

scholarly journals Sodium butyrate inhibits myogenesis by interfering with the transcriptional activation function of MyoD and myogenin.

1992 ◽  
Vol 12 (11) ◽  
pp. 5123-5130 ◽  
Author(s):  
L A Johnston ◽  
S J Tapscott ◽  
H Eisen
Keyword(s):  
Sodium Butyrate ◽  
Transcriptional Activation ◽  
Activation Function ◽  
Muscle Differentiation ◽  
Transcriptional Activators ◽  
Present Evidence ◽  
Dna Transcription ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix

Sodium butyrate reversibly inhibits muscle differentiation and blocks the expression of many muscle-specific genes in both proliferating myoblasts and differentiated myotubes. We investigated the role of the basic helix-loop-helix (bHLH) myogenic determinator proteins MyoD and myogenin in this inhibition. Our data suggest that both MyoD and myogenin are not able to function as transcriptional activators in the presence of butyrate, although both apparently retain the ability to bind DNA. Transcription of MyoD itself is extinguished in butyrate-treated myoblasts and myotubes, an effect that may be due to the inability of MyoD to autoactivate its own transcription. We present evidence that the HLH region of MyoD is essential for butyrate inhibition of MyoD. In contrast to MyoD and myogenin, butyrate does not inhibit the ubiquitous basic HLH protein E2-5 from functioning as a transcriptional activator.

scholarly journals SRF is a nonhistone methylation target of KDM2B and SET7 in the regulation of skeletal muscle differentiation

2021 ◽  
Vol 53 (2) ◽  
pp. 250-263
Author(s):  
Duk-Hwa Kwon ◽  
Joo-Young Kang ◽  
Hosouk Joung ◽  
Ji-Young Kim ◽  
Anna Jeong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Differentiation ◽  
Muscle Cell ◽  
Transcriptional Activation ◽  
Serum Response Factor ◽  
Muscle Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Muscle Cell Differentiation ◽  
Lysine Residues ◽  
Serum Response

AbstractThe demethylation of histone lysine residues, one of the most important modifications in transcriptional regulation, is associated with various physiological states. KDM2B is a demethylase of histones H3K4, H3K36, and H3K79 and is associated with the repression of transcription. Here, we present a novel mechanism by which KDM2B demethylates serum response factor (SRF) K165 to negatively regulate muscle differentiation, which is counteracted by the histone methyltransferase SET7. We show that KDM2B inhibited skeletal muscle differentiation by inhibiting the transcription of SRF-dependent genes. Both KDM2B and SET7 regulated the balance of SRF K165 methylation. SRF K165 methylation was required for the transcriptional activation of SRF and for the promoter occupancy of SRF-dependent genes. SET7 inhibitors blocked muscle cell differentiation. Taken together, these data indicate that SRF is a nonhistone target of KDM2B and that the methylation balance of SRF as maintained by KDM2B and SET7 plays an important role in muscle cell differentiation.

scholarly journals RhoA GTPase and Serum Response Factor Control Selectively the Expression of MyoD without Affecting Myf5 in Mouse Myoblasts

1998 ◽  
Vol 9 (7) ◽  
pp. 1891-1902 ◽  
Author(s):  
Gilles Carnac ◽  
Michael Primig ◽  
Magali Kitzmann ◽  
Philippe Chafey ◽  
David Tuil ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Proteins ◽  
Transcriptional Activation ◽  
Serum Response Factor ◽  
Muscle Differentiation ◽  
Dominant Negative ◽  
Response Factor ◽  
Rhoa Protein ◽  
Myod Gene ◽  
Serum Response

MyoD and Myf5 belong to the family of basic helix-loop-helix transcription factors that are key operators in skeletal muscle differentiation. MyoD and Myf5 genes are selectively activated during development in a time and region-specific manner and in response to different stimuli. However, molecules that specifically regulate the expression of these two genes and the pathways involved remain to be determined. We have recently shown that the serum response factor (SRF), a transcription factor involved in activation of both mitogenic response and muscle differentiation, is required for MyoD gene expression. We have investigated here whether SRF is also involved in the control of Myf5 gene expression, and the potential role of upstream regulators of SRF activity, the Rho family G-proteins including Rho, Rac, and CDC42, in the regulation of MyoD and Myf5. We show that inactivation of SRF does not alter Myf5 gene expression, whereas it causes a rapid extinction of MyoD gene expression. Furthermore, we show that RhoA, but not Rac or CDC42, is also required for the expression of MyoD. Indeed, blocking the activity of G-proteins using the general inhibitor lovastatin, or more specific antagonists of Rho proteins such as C3-transferase or dominant negative RhoA protein, resulted in a dramatic decrease of MyoD protein levels and promoter activity without any effects on Myf5 expression. We further show that RhoA-dependent transcriptional activation required functional SRF in C2 muscle cells. These data illustrate that MyoD and Myf5 are regulated by different upstream activation pathways in which MyoD expression is specifically modulated by a RhoA/SRF signaling cascade. In addition, our results establish the first link between RhoA protein activity and the expression of a key muscle regulator.

scholarly journals SRF is a non-histone methylation target of KDM2B and SET7 in the regulation of myogenesis

2020 ◽  
Author(s):  
Hosouk Joung ◽  
Joo-Young Kang ◽  
Ji-Young Kim ◽  
Duk-Hwa Kwon ◽  
Anna Jeong ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Muscle Cell ◽  
Transcriptional Activation ◽  
Serum Response Factor ◽  
Muscle Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Muscle Cell Differentiation ◽  
Histone H3k4 ◽  
Promoter Occupancy ◽  
Serum Response

AbstractDemethylation of histone lysines, one of the most important modifications in transcriptional regulation, is associated with various physiological states. KDM2B is a histone H3K4, H3K36, and H3K79 demethylase associated with the repression of transcription. Here, we present a novel mechanism by which KDM2B demethylates serum response factor (SRF) K165 to negatively regulate muscle differentiation, which is counteracted by histone methyltransferase SET7. We show that KDM2B inhibited skeletal muscle differentiation by inhibiting the transcription of SRF-dependent genes. Both KDM2B and SET7 regulated the balance of SRF K165 methylation. SRF K165 methylation was required for the transcriptional activation of SRF and for the promoter occupancy of SRF-dependent genes. SET7 inhibitors blocked muscle cell differentiation. Taken together, these data indicate that SRF is a non-histone target of KDM2B and that the methylation balance of SRF maintained by KDM2B and SET7 plays an important role in muscle cell differentiation.

Sodium butyrate inhibits myogenesis by interfering with the transcriptional activation function of MyoD and myogenin

1992 ◽  
Vol 12 (11) ◽  
pp. 5123-5130
Author(s):  
L A Johnston ◽  
S J Tapscott ◽  
H Eisen
Keyword(s):  
Sodium Butyrate ◽  
Transcriptional Activation ◽  
Activation Function ◽  
Muscle Differentiation ◽  
Transcriptional Activators ◽  
Present Evidence ◽  
Dna Transcription ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix

Sodium butyrate reversibly inhibits muscle differentiation and blocks the expression of many muscle-specific genes in both proliferating myoblasts and differentiated myotubes. We investigated the role of the basic helix-loop-helix (bHLH) myogenic determinator proteins MyoD and myogenin in this inhibition. Our data suggest that both MyoD and myogenin are not able to function as transcriptional activators in the presence of butyrate, although both apparently retain the ability to bind DNA. Transcription of MyoD itself is extinguished in butyrate-treated myoblasts and myotubes, an effect that may be due to the inability of MyoD to autoactivate its own transcription. We present evidence that the HLH region of MyoD is essential for butyrate inhibition of MyoD. In contrast to MyoD and myogenin, butyrate does not inhibit the ubiquitous basic HLH protein E2-5 from functioning as a transcriptional activator.

scholarly journals CREB-mediated transcriptional activation of NRMT1 drives muscle differentiation

2021 ◽  
Author(s):  
John G Tooley ◽  
James P Catlin ◽  
Christine E Schaner Tooley
Keyword(s):  
Cell Differentiation ◽  
Muscle Cell ◽  
Transcriptional Activation ◽  
Type I Collagen ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Serum Starvation ◽  
Type I ◽  
Muscle Cell Differentiation

The N-terminal methyltransferase NRMT1 is an important regulator of protein-DNA interactions and plays a role in many cellular processes, including mitosis, cell cycle progression, chromatin organization, DNA damage repair, and transcriptional regulation. Accordingly, loss of NRMT1 results in both developmental pathologies and oncogenic phenotypes. Though NRMT1 plays such important and diverse roles in the cell, little is known about its own regulation. To better understand the mechanisms governing NRMT1 expression, we first identified its predominant transcriptional start site and minimal promoter region with predicted transcription factor motifs. We then used a combination of luciferase and binding assays to confirm CREB1 as the major regulator of NRMT1 transcription. We tested which conditions known to activate CREB1 also activated NRMT1 transcription, and found CREB1-mediated NRMT1 expression was increased during recovery from serum starvation and muscle cell differentiation. To determine how NRMT1 expression affects myoblast differentiation, we used CRISPR/Cas9 technology to knock out NRMT1 expression in immortalized C2C12 mouse myoblasts. C2C12 cells depleted of NRMT1 lacked Pax7 expression and were unable to proceed down the muscle differentiation pathway. Instead, they took on characteristics of C2C12 cells that have transdifferentiated into osteoblasts, including increased alkaline phosphatase and type I collagen expression and decreased proliferation. These data implicate NRMT1 as an important downstream target of CREB1 during muscle cell differentiation.

Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity

2019 ◽  
Vol 476 (24) ◽  
pp. 3705-3719 ◽  
Author(s):  
Avani Vyas ◽  
Umamaheswar Duvvuri ◽  
Kirill Kiselyov
Keyword(s):  
Oxidative Stress ◽  
Head And Neck ◽  
Transcriptional Activation ◽  
Platinum Resistance ◽  
Mrna Levels ◽  
Strong Positive Correlation ◽  
Platinum Compounds ◽  
Copper Chelation ◽  
Novel Approach ◽  
Cancer Models

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.

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