Postsynaptic chromatin is under neural control at the neuromuscular junction

Abstract

In adult skeletal muscle, the nicotinic acetylcholine receptor (AChR) specifically accumulates at the neuromuscular junction, to allow neurotransmission. This clustering is paralleled by a compartmentalization of AChR genes expression to subsynaptic nuclei, which acquire a unique gene expression program and a specific morphology in response to neural cues. Our results demonstrate that neural agrin-dependent reprogramming of myonuclei involves chromatin remodelling, histone hyperacetylation and histone hyperphosphorylation. Activation of AChR genes in subsynaptic nuclei is mediated by the transcription factor GABP. Here we demonstrate that upon activation, GABP recruits the histone acetyl transferase (HAT) p300 on the AChR epsilon subunit promoter, whereas it rather recruits the histone deacetylase HDAC1 when the promoter is not activated. Moreover, the HAT activity of p300 is required in vivo for AChR expression. GABP therefore couples chromatin hyperacetylation and AChR activation by neural factors in subsynaptic nuclei.