The LIM domain protein nTRIP6 acts as a co-repressor for the transcription factor MEF2C in myoblasts

Abstract

The transcription factor Myocyte enhancer factor 2C (MEF2C) plays a key role in the late differentiation of skeletal muscle progenitor cells, the so-called myoblasts. During myoblast differentiation, both MEF2C expression and transcriptional activity are regulated. We have reported that nTRIP6, the nuclear isoform of the focal adhesion LIM domain protein TRIP6, acts as an adaptor transcriptional co-activator for several transcription factors. It interacts with the promoter-bound transcription factors and consequently mediates the recruitment of other co-activators. Based on a described interaction between MEF2C and TRIP6 in a yeast-two-hybrid screen, we hypothesised a co-regulatory function of nTRIP6 for MEF2C. In proliferating myoblasts, nTRIP6 interacted with MEF2C and was recruited together with MEF2C to the MEF2-binding regions of the MEF2C target genes Myom2, Mb, Tnni2 and Des. Silencing nTRIP6 or preventing its interaction with MEF2C increased MEF2C transcriptional activity and increased the expression of these MEF2C target genes. Thus, nTRIP6 acts as a co-repressor for MEF2C. Mechanistically, nTRIP6 mediated the recruitment of the class IIa histone deacetylase HDAC5 to the MEF2C-bound promoters. In conclusion, our results unravel a transcriptional co-repressor function for nTRIP6. This adaptor co-regulator can thus exert either co-activator or co-repressor functions, depending on the transcription factor it interacts with.

Nuclear Pores Regulate Muscle Development and Maintenance by Assembling a Localized Mef2C Complex

“…Trip6 is an adaptor protein that shuttles between focal adhesions and the nucleus, and acts as a transcriptional co-regulator (Lin and Lin, 2011). Although the function of Trip6 in the regulation of muscle physiology has not been investigated, this protein is known to interact with factors that play key roles in myogenesis and muscle development, such as Mef2C (Kemler et al, 2016) and the LIMdomain proteins FHL3 and ILF3 (Cottle et al, 2007; Shi et al, 2005). Trip6 functions and interaction partners suggest that Nup210 modulation of gene expression might involve this transcriptional co-regulator.…”

“…Recently, Trip6 was identified to interact with the transcription factor Mef2C (Kemler et al, 2016), a critical regulator of skeletal and cardiac muscle development (Potthoff and Olson, 2007). Similar to Nup210, Mef2C is dispensable for early embryonic muscle development but essential for myofiber growth, maturation, and survival (Hinits and Hughes, 2007; Hinits et al, 2012; Lin et al, 1997; Potthoff et al, 2007).…”

Mef2 and the skeletal muscle differentiation program

“…Shortly after its discovery it was apparent that protein interactions were significant to Mef2 function: it both dimerised and interacted with the MRFs [8,41,142]. in myoblasts [146]. Intriguingly, TRIP6 can interact with Nup210 in a nuclear pore complex implicated in muscle gene expression control [147].…”

Novel function of TRIP6, in brain ciliogenesis

“…whether the differentiation defects are a consequence of the compromized cilia formation or are caused by trip6 deletion independently. TRIP6 also acts as a transcription regulator via a nuclear isoform (Kassel et al, 2004;Diefenbacher et al, 2008;Diefenbacher et al, 2014;Kemler et al, 2016) and thus could regulate differentiation programmes. However, we have not detected nuclear TRIP6 in the brain cells examined.…”