M-cadherin is a skeletal muscle-specific transmembrane protein mediating the cell-cell adhesion of myoblasts during myogenesis. It is expressed in the proliferating satellite cells and highly induced by myogenic regulatory factors (MRFs) during terminal myogenic differentiation. Several conserved cis-elements, including 5 E-boxes, 2 GC boxes, and 1 conserved downstream element (CDE) were identified in the M-cadherin proximal promoter. We found that E-box-3 and -4 close to the transcription initiation site (TIS) mediated most of its transactivation by MyoD, the strongest myogenic MRF. Including of any one of the other E-boxes restored the full activation by MyoD, suggesting an essential collaboration between E-boxes. Stronger activation of M-cadherin promoter than that of muscle creatine kinase (MCK) by MyoD was observed regardless of culture conditions and the presence of E47. Furthermore, MyoD/E47 heterodimer and MyoD ∼ E47 fusion protein achieved similar levels of activation in differentiation medium (DM), suggesting high affinity of MyoD/E47 to E-boxes 3/4 under DM. We also found that GC boxes and CDE positively affected MyoD mediated activation. The CDE element was predicted to be the target of the chromatin-modifying factor Meis1/Pbx1 heterodimer. Knockdown of Pbx1 significantly reduced the expression level of M-cadherin, but increased that of N-cadherin. Using ChIP assay, we further found significant reduction in MyoD recruitment to M-cadherin promoter when CDE was deleted. Taken together, these observations suggest that the chromatin-modifying function of Pbx1/Meis1 is critical to M-cadherin promoter activation before MyoD is recruited to E-boxes to trigger transcription.
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In the brain, cocaine exposure results in mitochondrial DNA damage, depletion of ATP and increased oxidative stress, coupled with increased mitochondrial fission. Therapies preventing such bioenergetic impairment may hold promise in mitigating cocaine pathology and addiction. You can read more about this in the review by Thornton and colleagues (pp. 749–764) in this issue. Image provided by Claire Thornton.
Research Article|
February 26 2021
The cooperation of cis-elements during M-cadherin promoter activation
Yung-Jui Lin;
Yung-Jui Lin
*
Investigation, Methodology
Department of Life Sciences, National Central University, Jhongli 32001, Taiwan
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Chien-Han Kao;
Chien-Han Kao
*
Investigation, Methodology
Department of Life Sciences, National Central University, Jhongli 32001, Taiwan
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Sheng-Pin Hsiao;
Sheng-Pin Hsiao
Department of Life Sciences, National Central University, Jhongli 32001, Taiwan
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Shen-Liang Chen
Department of Life Sciences, National Central University, Jhongli 32001, Taiwan
Correspondence: Shen Liang Chen (slchen@cc.ncu.edu.tw)
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Publisher: Portland Press Ltd
Received:
July 07 2020
Revision Received:
January 21 2021
Accepted:
February 02 2021
Accepted Manuscript online:
February 02 2021
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2021
Biochem J (2021) 478 (4): 911–926.
Article history
Received:
July 07 2020
Revision Received:
January 21 2021
Accepted:
February 02 2021
Accepted Manuscript online:
February 02 2021
Citation
Yung-Jui Lin, Chien-Han Kao, Sheng-Pin Hsiao, Shen-Liang Chen; The cooperation of cis-elements during M-cadherin promoter activation. Biochem J 26 February 2021; 478 (4): 911–926. doi: https://doi.org/10.1042/BCJ20200535
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