The Hox transcription factor Ubx ensures somatic myogenesis by suppressing the mesodermal master regulator Twist

Abstract

Early determination factors and lineage-specific master regulators are essential for the specification of cell and tissue types. However, once a cell has committed to a specific fate, it is equally critical to restrict the activity of such factors to enable proper differentiation. In many studies the functional network for master regulators are under constant investigations. Yet, how these factors are silenced remains unclear. Using the Drosophila mesoderm as a model and a comparative genomic approach, we identified the Hox transcription factor (TF) Ultrabithorax (Ubx) to be critical for the repression of the mesodermal master regulator Twist (Twi). Mesoderm-specific Ubx loss-of-function experiments using CRISPR/Cas9 as well as overexpression experiments demonstrated that Ubx majorly impacts twi transcription. A detailed mechanistic analysis revealed that Ubx requires the function of the NK-homeodomain protein Tinman (Tin) but not the muscle differentiation factor Myocyte enhancer factor 2 (Mef2) to bind to the twi promoter. Furthermore, we found these TF interactions to be critical for silencing of the twi promoter region by recruiting the Polycomb DNA binding protein Pleiohomeotic (Pho). In sum, our study demonstrates that the Hox TF Ubx is a critical player in mediating the silencing of the mesodermal master regulator Twi, which is crucial for coordinated muscle differentiation.-3 -3

An atlas of spider development at single-cell resolution provides new insights into arthropod embryogenesis

“…Given the role of Dl in specifying ectodermal versus mesodermal fate, this strongly suggests that there is dynamic specification and sorting of ectodermal and mesodermal cells in the SAZ throughout opisthosomal segmentation. One other marker of cluster 3, Ubx-A , has been shown to suppress twist in somatic myogenesis, which raises the possibility that this Hox gene may also function in a similar manner in the SAZ [121].…”

Twist regulates Yorkie activity to guide lineage reprogramming of syncytial alary muscles

“…Twi function and cellular plasticity are connected mainly due to its role as one of the transcriptional master regulators of epithelial-to-mesenchymal states (EMT), crucially required for embryonic morphogenesis and often linked to metastasis in various cancer models (Lu and Kang, 2019). In terms of myogenic cell fate plasticity, it is known that prolonged Twi expression negatively regulates muscle cell differentiation as well as adult flight muscle development (Anant et al, 1998;Cripps and Olson, 1998;Domsch et al, 2021), whereas forced expression of vertebrate Twi proteins can even reverse myogenic differentiation in vitro (Hjiantoniou et al, 2008;Li et al, 2019;Liu et al, 2017;Mastroyiannopoulos et al, 2013) and appears to play a role during regeneration of craniofacial muscles (Zhao et al, 2020). Here, we provide evidence that Twi mediates the reversal of syncytial cell fate, uncovering an unknown function of Twi in Drosophila muscles during metamorphosis.…”

Integrative Role of 14-3-3ε in Sleep Regulation

“…When interacting with Pho, Ubx can stabilize lineage choice through suppressing the multipotency encoded in the genome [ 38 ]. Regulated by polycomb complex, Ubx is a repressor of alternative cell fates within the mesoderm, and it also maintains normal muscle differentiation by repressing Twi [ 39 ]. In this study, Ubx takes part in regulating fly sleep by cooperating with 14-3-3ε .…”