Abstract
Skeletal muscle differentiation is triggered by a unique family of myogenic basic helix-loop-helix transcription factors, including MyoD, MRF-4, Myf-5, and Myogenin. These transcription factors bind promoters and distant regulatory regions, including E-box elements, of genes whose expression is restricted to muscle cells. Other E-box binding zinc finger proteins target the same DNA response elements, however, their function in muscle development and regeneration is still unknown. Here, we show that the transcription factor zinc finger E-box-binding homeobox 2 (Zeb2, Sip-1, Zfhx1b) is present in skeletal muscle tissues. We investigate the role of Zeb2 in skeletal muscle differentiation using genetic tools and transgenic mouse embryonic stem cells, together with single-cell RNA-sequencing and in vivo muscle engraftment capability. We show that Zeb2 over-expression has a positive impact on skeletal muscle differentiation in pluripotent stem cells and adult myogenic progenitors. We therefore propose that Zeb2 is a novel myogenic regulator and a possible target for improving skeletal muscle regeneration. The non-neural roles of Zeb2 are poorly understood.
Highlights
Zeb2 is a two-handed zinc-finger/homeodamin protein closely related to Zeb1 [1]
The Upregulation of Zeb2 Positively Affects Myogenic Markers in mouse embryonic stem cells (mESCs) Subjected to Skeletal Muscle Differentiation
The MyomiR expression profiles were altered in Zeb2-null and R26_Zeb2 mESCs subjected to skeletal muscle differentiation
Summary
Zeb is a two-handed zinc-finger/homeodamin protein closely related to Zeb (δEF1, Zfhx1a) [1]. Both factors regulate gene transcription through similar, E-box-mediated DNA-binding [2,3]. Zeb is a strong binder of activated Smads, making it a nuclear fine-tuner of the transcriptional response to TGFβ/Nodal-Activin and BMP stimulation of cells [1,6,7,8]. This role has been shown to result, depending on cell stage/type, in the generation of anti-BMP, and anti-Wnt, anti-Notch, and anti-Sox activities in embryonic development and cell differentiation/maturation, best documented in embryonic myelinogenesis, and adult Schwann cell differentiation and remyelination [9,10,11]. Heterozygous ZEB2 mutations in humans cause Mowat-Wilson Syndrome (OMIM #235730), involving severe intellectual disability, Hirschsprung disease, epilepsy, and other developmental defects, with some patients presenting with musculoskeletal anomalies [8,12,13]
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