University of Massachusetts Medical School Faculty Publications

Title

The classic metal-sensing transcription factor MTF1 promotes myogenesis in response to copper

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Department of Molecular, Cell, and Cancer Biology; Imbalzano Lab

Publication Date

2019-12-01

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology | Nucleic Acids, Nucleotides, and Nucleosides

Abstract

Metal-regulatory transcription factor 1 (MTF1) is a conserved metal-binding transcription factor in eukaryotes that binds to conserved DNA sequence motifs, termed metal response elements. MTF1 responds to both metal excess and deprivation, protects cells from oxidative and hypoxic stresses, and is required for embryonic development in vertebrates. To examine the role for MTF1 in cell differentiation, we use multiple experimental strategies [including gene knockdown (KD) mediated by small hairpin RNA and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), immunofluorescence, chromatin immunopreciptation sequencing, subcellular fractionation, and atomic absorbance spectroscopy] and report a previously unappreciated role for MTF1 and copper (Cu) in cell differentiation. Upon initiation of myogenesis from primary myoblasts, both MTF1 expression and nuclear localization increased. Mtf1 KD impaired differentiation, whereas addition of nontoxic concentrations of Cu(+)-enhanced MTF1 expression and promoted myogenesis. Furthermore, we observed that Cu(+) binds stoichiometrically to a C terminus tetra-cysteine of MTF1. MTF1 bound to chromatin at the promoter regions of myogenic genes, and Cu addition stimulated this binding. Of note, MTF1 formed a complex with myogenic differentiation (MYOD)1, the master transcriptional regulator of the myogenic lineage, at myogenic promoters. These findings uncover unexpected mechanisms by which Cu and MTF1 regulate gene expression during myoblast differentiation.

Keywords

ChIP-Seq, copper binding, myogenic differentiation 1

DOI of Published Version

10.1096/fj.201901606R

Source

Tavera-Montañez C, Hainer SJ, Cangussu D, Gordon SJV, Xiao Y, Reyes-Gutierrez P, Imbalzano AN, Navea JG, Fazzio TG, Padilla-Benavides T. The classic metal-sensing transcription factor MTF1 promotes myogenesis in response to copper. FASEB J. 2019 Dec;33(12):14556-14574. doi: 10.1096/fj.201901606R. Epub 2019 Nov 5. PMID: 31690123; PMCID: PMC6894080. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

PubMed ID

31690123

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