Genome‐wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis

Abstract

Adult skeletal muscles can regenerate after injury, due to the presence of satellite cells, a quiescent population of myogenic progenitor cells. Once activated, satellite cells repair the muscle damage by undergoing myogenic differentiation. The myogenic regulatory factors (MRFs) coordinate the process of progenitor differentiation in cooperation with other families of transcription factors (TFs). The Six1 and Six4 homeodomain TFs are expressed in developing and adult muscle and Six1 is critical for embryonic and adult myogenesis. However, the lack of a muscle developmental phenotype in Six4-null mice, which has been attributed to compensation by other Six family members, has discouraged further assessment of the role of Six4 during adult muscle regeneration. By employing genome-wide approaches to address the function of Six4 during adult skeletal myogenesis, we have identified a core set of muscle genes coordinately regulated in adult muscle precursors by Six4 and the MRF MyoD. Throughout the genome of differentiating adult myoblasts, the cooperation between Six4 and MyoD is associated with chromatin repressive mark removal by Utx, a demethylase of histone H3 trimethylated at lysine 27. Among the genes coordinately regulated by Six4 and MyoD are several genes critical for proper in vivo muscle regeneration, implicating a role of Six4 in this process. Using in vivo RNA interference of Six4, we expose an uncompensated function of this TF during muscle regeneration. Together, our results reveal a role for Six4 during adult muscle regeneration and suggest a widespread mechanism of cooperation between Six4 and MyoD.

Polycomb/Trithorax Antagonism: Cellular Memory in Stem Cell Fate and Function

“…Besides ESCs and hematopoietic cells, the mechanism leading to TrxG complex recruitment has been thoroughly explored in muscle differentiation (Figure 3). Upon the decision to differentiate in muscle progenitors, the Six4 homeobox protein recruits Trr-COMPASS to specific genes involved in muscle development whereby the demethylase subunit UTX removes the repressive H3K27me3 mark to activate transcription (Chakroun et al, 2015;Seenundun et al, 2010). At the same time, Trx-COMPASS is targeted to muscle-specific genes through its interaction with the ubiquitously expressed TF Mef2D (Rampalli et al, 2007), whereas the SWI/SNF complex is recruited through a direct interaction between its BAF60C subunit and the muscle-specific transcriptional activator MyoD (Forcales et al, 2012).…”

ISL1 and JMJD3 synergistically control cardiac differentiation of embryonic stem cells

“…One possible way is that these epigenetic enzymes may interact with lineage specific transcription factors in a context dependent manner. For example, UTX, a histone H3K27 demethylase, interacts with TBX5 to activate the cardiac development program, but partners with MYOD and SIX4 to regulate myogenesis (23,24). BAF60c, a subunit of the Swi/Snf-like Brg1/Brm-associated (BAF) chromatin remodeling complexes, also interacts with different transcription factors, such as GATA4, NKX2-5 and TBX5, to activate distinct group of genes during heart development (25).…”

Dynamics of transcriptional (re)-programming of syncytial nuclei in developing muscles

“…We conclude that the generic muscle differentiation and morphological identity programmes are regulated independently of each other. Transcriptional control of the generic aspects of skeletal muscle development in vertebrates involves several transcription factors that act as muscle iTFs in Drosophila , including Nautilus/MyoD, Eya, Six and Col/EBF proteins [12, 52–54]. Our data in Drosophila plead for investigating whether muscle identity and generic differentiation programmes also run in parallel in vertebrates.…”