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

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.-Tavera-

lncRNA OTUD6B-AS1 Exacerbates As2O3-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2

“…Interestingly, treatment with As 2 O 3 clearly increased MTF1 expression. In addition, apocynin, a NADPH oxidase inhibitor, eliminated this increase of MTF1 expression, consistent with the reports of Tavera-Montanez et al that MTF1 levels were increased following exposure to toxic heavy metals [ 44 ]. Furthermore, we found that MTF1 knockdown eliminated the As 2 O 3 -induced increase of lncRNA OTUD6B-AS1 expression.…”

Gawky modulates MTF-1-mediated transcription activation and metal discrimination

“…Mouse embryos lacking MTF-1 show embryonic lethality probably due to the dysregulation of γ-glutamylcysteine synthetase ( γ-GCS ), an essential MTF-1 target gene in glutathione biosynthesis ( 27 ). A recent study demonstrated that MTF-1 regulates myoblast differentiation via direct interaction with the myogenic gene promoter ( 28 ). These studies suggest that MTF-1 is an important factor involved in the regulation of a diverse set of genes, thereby protecting cells from various stressors.…”

Dynamic regulatory module networks for inference of cell type-specific transcriptional networks

“…Importantly, we found that several TFs have known roles in the stage in which they are found significant, e.g., Nfe2fl2 in ESC and pre-IPSC module 6, which is known to play an important role in the embryonic stem cell state [17], and Mycn and Esrrb in the pre-IPSC module 6, which are both known to be important for early embryonic stages. We also found several muscle and mesodermal factors associated with MEF (Foxl1 [18], Mtf1 [19] in module 6), MEF48 (Osr1 [20], Left1 [21] in module 5), and both MEF and MEF48 (Sox5 [22] in module 5).…”