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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetylation
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Animals
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Blotting, Western
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Cell Line
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Chromatin / enzymology
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Chromatin / genetics*
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Chromatin Immunoprecipitation
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Drosophila Proteins / genetics*
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Drosophila Proteins / metabolism
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Drosophila melanogaster / cytology
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Drosophila melanogaster / enzymology
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Drosophila melanogaster / genetics*
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Gene Expression Regulation*
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Gene Silencing
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Histone Deacetylase 1 / genetics*
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Histone Deacetylase 1 / metabolism
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Histone Deacetylases / genetics*
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Histone Deacetylases / metabolism
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Histones / genetics*
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Histones / metabolism
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Lamin Type B / antagonists & inhibitors
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Lamin Type B / genetics
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Lamin Type B / metabolism
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Multigene Family
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Nuclear Lamina / enzymology
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Nuclear Lamina / genetics*
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RNA, Double-Stranded / genetics
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Transcription, Genetic
Substances
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Chromatin
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Drosophila Proteins
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Histones
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Lamin Type B
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RNA, Double-Stranded
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HDAC1 protein, Drosophila
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Histone Deacetylase 1
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Histone Deacetylases
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histone deacetylase 3
Grants and funding
This study was supported by grant number 0960531 from the National Science Foundation (MCB Division of Molecular and Cellular Biosciences),
http://www.nsf.gov/; Russian Foundation for Basic Research grant number 10-04-00669-a,
http://www.rfbr.ru; grant for Molecular and Cellular Biology from Russian Academy of Sciences,
www.ras.ru. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.