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

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 lamina 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.

Nuclear envelope, chromatin organizers, histones, and DNA: The many achilles heels exploited across cancers

“…Notably, lamin loss leads to an anomalous distribution of PcG proteins, eventually resulting in dysregulated gene expression and accelerated cancer progression. HDAC2 also plays an active role in heterochromatinization by interacting with LMNA at the nuclear periphery (Mattioli et al, 2018;Santi et al, 2020;Murray-Nerger and Cristea, 2021). However, the molecular mechanisms involving lamin-mediated regulation of inactive H3K9me3 and H3K27me3 and active H3K4me3 marks are yet to be uncovered.…”

Signaling pathways of adipose stem cell-derived exosomes promoting muscle regeneration

“…[ 87 ] Lamin A/C identified in ASC-exos combines with HDAC2 to promote the interaction between p300/CBP-associated factor (PCAF) and MyoD. [ 88 ] Akt1/2 directly phosphorylates p300 to allow the binding of MyoD to p300 and PCAF and promote transcription. [ 89 ] PI3K/Akt can induce the phosphorylation and transcriptional activity of MEF2 to assist MRFs.…”

“…PI3K/Akt stimulates upregulation of stathmin, which is essential for MyoD expression [87] . Lamin A/C identified in ASC-exos combines with HDAC2 to promote the interaction between p300/CBP-associated factor (PCAF) and MyoD [88] . Akt1/2 directly phosphorylates p300 to allow the binding of MyoD to p300 and PCAF and promote transcription [89] .…”

Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

“…This condition is not only due to the presence of mutated lamin A/C, but also to co-occurrence of variants in genes encoding for proteins of the nuclear envelope, as recently reported in EDMD2 and EDMD2-like patients [ 140 ]. Moreover, dysregulation of epigenetic enzymes as the Polycomb group transcriptional repressors and the acetyltransferase HDAC2 has been implicated in aberrant gene expression in EDMD2 models [ 142 , 143 , 144 ]. Among affected genes, also desmin has been identified, and altered desmin expression has been shown to impair myogenic differentiation of laminopathic myoblasts [ 141 ].…”