Abstract
Theoretical models suggest that gene silencing at the nuclear periphery may involve “closing” of chromatin by transcriptional repressors, such as histone deacetylases (HDACs). Here we provide experimental evidence confirming these predictions. Histone acetylation, chromatin compactness, and gene repression in lamina-interacting multigenic chromatin domains were analyzed in Drosophila S2 cells in which B-type lamin, diverse HDACs, and lamina-associated proteins were downregulated by dsRNA. Lamin depletion resulted in decreased compactness of the repressed multigenic domain associated with its detachment from the lamina and enhanced histone acetylation. Our data reveal the major role for HDAC1 in mediating deacetylation, chromatin compaction, and gene silencing in the multigenic domain, and an auxiliary role for HDAC3 that is required for retention of the domain at the lamina. These findings demonstrate the manifold and central involvement of class I HDACs in regulation of lamina-associated genes, illuminating a mechanism by which these enzymes can orchestrate normal and pathological development.
Highlights
Numerous clusters of genes, co-expressed in development or in disease, have been described in diverse eukaryotes [1,2,3]
A theoretical model [14] suggests that accessory polypeptides such as Lamin B receptor (LBR) and LEM domain proteins tether diverse transcriptional repressors to the lamin meshwork thereby creating a ‘‘silencing environment’’, which acts on chromatin that is ensnared at the nuclear periphery by chromatin/lamina-bridging factors such as barrier-to-autointegration factor (BAF) [14,15]
A broad-range histone deacetylases (HDACs) inhibitor, trichostatin A (TSA), increases histone acetylation at the nuclear periphery [23] and attenuates repression of lamina-tethered genes [13], supporting the idea that HDACs may mediate gene repression at the nuclear lamina where these enzymes can accumulate due to their affinity to the LEM domain proteins and BAF [15,24,25]
Summary
Co-expressed in development or in disease, have been described in diverse eukaryotes [1,2,3]. By taking advantage of the well-described model of testis-specific multigenic chromatin domain repressed by a nuclear lamina-dependent mechanism in Drosophila somatic cells [1,7,34], we show that this repression is linked to histone deacetylation and chromatin condensation.
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