PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation

Spartaco Santi,Cristina Capanni,Giovanna Lattanzi,Vittoria Cenni,Elisabetta Mattioli

doi:10.3390/cells9071735

Spartaco Santi, Cristina Capanni + Show 3 more

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https://doi.org/10.3390/cells9071735

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Abstract

Lamin A/C has been implicated in the epigenetic regulation of muscle gene expression through dynamic interaction with chromatin domains and epigenetic enzymes. We previously showed that lamin A/C interacts with histone deacetylase 2 (HDAC2). In this study, we deepened the relevance and regulation of lamin A/C-HDAC2 interaction in human muscle cells. We present evidence that HDAC2 binding to lamin A/C is related to HDAC2 acetylation on lysine 75 and expression of p300-CBP associated factor (PCAF), an acetyltransferase known to acetylate HDAC2. Our findings show that lamin A and farnesylated prelamin A promote PCAF recruitment to the nuclear lamina and lamin A/C binding in human myoblasts committed to myogenic differentiation, while protein interaction is decreased in differentiating myotubes. Interestingly, PCAF translocation to the nuclear envelope, as well as lamin A/C-PCAF interaction, are reduced by transient expression of lamin A mutated forms causing Emery Dreifuss muscular dystrophy. Consistent with this observation, lamin A/C interaction with both PCAF and HDAC2 is significantly reduced in Emery–Dreifuss muscular dystrophy myoblasts. Overall, these results support the view that, by recruiting PCAF and HDAC2 in a molecular platform, lamin A/C might contribute to regulate their epigenetic activity required in the early phase of muscle differentiation.

Highlights

A fine regulation of acetyltransferases (HAT) and histone deacetylases (HDACs) activity is at the basis of all physiological cellular processes including skeletal myogenesis [1,2]
We found that p300-CBP associated factor (PCAF) targeting to the nuclear lamina was reduced by LMNA mutations causing EDMD2 and lamin A/C-histone deacetylase 2 (HDAC2) interaction was impaired in EDMD2 myoblasts
HDAC2 was confirmed by an anti-acetyl lysine specific antibody (Figure 1a). These results demonstrated that HDAC2 acetylation on lysine 75 promotes its binding to lamin A/C

Summary

Introduction

A fine regulation of acetyltransferases (HAT) and histone deacetylases (HDACs) activity is at the basis of all physiological cellular processes including skeletal myogenesis [1,2]. HDAC2 function is regulated through its acetylation, a modification that, in cardiomyocytes, is finely balanced by acetyltransferase p300-CBP associated factor (PCAF) and HDAC5 activity [4]. HDAC2 and PCAF are involved in the early phase of muscle differentiation by coordinating MyoD acetylation and its transactivation activity [5,6]. When myoblasts exit from the cell cycle, PCAF replaces HDAC2 and acetylates MyoD, inducing muscle gene transcription [6,9]

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