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Mol Cell Biol. 2015 Feb;35(4):662-74. doi: 10.1128/MCB.01102-14. Epub 2014 Dec 8.

Panspecies small-molecule disruptors of heterochromatin-mediated transcriptional gene silencing.

Author information

1
Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom.
2
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
3
Institute for Research in Immunology and Cancer, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
4
Instituto de Hortofruticultura Subtropical y Mediterránea La Mayora, Universidad de Málaga, Consejo Superior de Investigaciones Científicas (IHSM-UMA-CSIC), Area de Genética, Campus de Teatinos, Málaga, Spain.
5
Department of Molecular Biology, Science III, Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.
6
Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden.
7
Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom Institute for Research in Immunology and Cancer, Department of Medicine, Université de Montréal, Montréal, Québec, Canada md.tyers@umontreal.ca robin.allshire@ed.ac.uk.
8
Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom md.tyers@umontreal.ca robin.allshire@ed.ac.uk.

Abstract

Heterochromatin underpins gene repression, genome integrity, and chromosome segregation. In the fission yeast Schizosaccharomyces pombe, conserved protein complexes effect heterochromatin formation via RNA interference-mediated recruitment of a histone H3 lysine 9 methyltransferase to cognate chromatin regions. To identify small molecules that inhibit heterochromatin formation, we performed an in vivo screen for loss of silencing of a dominant selectable kanMX reporter gene embedded within fission yeast centromeric heterochromatin. Two structurally unrelated compounds, HMS-I1 and HMS-I2, alleviated kanMX silencing and decreased repressive H3K9 methylation levels at the transgene. The decrease in methylation caused by HMS-I1 and HMS-I2 was observed at all loci regulated by histone methylation, including centromeric repeats, telomeric regions, and the mating-type locus, consistent with inhibition of the histone deacetylases (HDACs) Clr3 and/or Sir2. Chemical-genetic epistasis and expression profiles revealed that both compounds affect the activity of the Clr3-containing Snf2/HDAC repressor complex (SHREC). In vitro HDAC assays revealed that HMS-I1 and HMS-I2 inhibit Clr3 HDAC activity. HMS-I1 also alleviated transgene reporter silencing by heterochromatin in Arabidopsis and a mouse cell line, suggesting a conserved mechanism of action. HMS-I1 and HMS-I2 bear no resemblance to known inhibitors of chromatin-based activities and thus represent novel chemical probes for heterochromatin formation and function.

PMID:
25487573
PMCID:
PMC4301722
DOI:
10.1128/MCB.01102-14
[Indexed for MEDLINE]
Free PMC Article

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