Abstract
Coating of the X chromosome by Xist RNA is an essential trigger for X inactivation. However, little is known about the early chromatin remodeling events that transform this signal into transcriptional silencing. Here we report that methylation of histone H3 lysine 9 on the inactive X chromosome occurs immediately after Xist RNA coating and before transcriptional inactivation of X-linked genes. X-chromosomal H3 Lys-9 methylation occurs during the same window of time as H3 Lys-9 hypoacetylation and H3 Lys-4 hypomethylation. Histone H3 modifications thus represent the earliest known chromatin changes during X inactivation. We also identify a unique "hotspot" of H3 Lys-9 methylation 5' to Xist, and we propose that this acts as a nucleation center for Xist RNA-dependent spread of inactivation along the X chromosome via H3 Lys-9 methylation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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A Kinase Anchor Proteins
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Acetylation
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Adaptor Proteins, Signal Transducing
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Animals
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Differentiation / physiology*
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Cells, Cultured
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Chromatin / metabolism*
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Chromosomal Proteins, Non-Histone*
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Cyclin-Dependent Kinase Inhibitor p27
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dosage Compensation, Genetic*
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Enzyme Inhibitors / metabolism
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Female
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Fibroblasts / physiology
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Gene Silencing
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Histones / metabolism*
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In Situ Hybridization, Fluorescence
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Male
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Methyl-CpG-Binding Protein 2
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Methylation
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Mice
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Minor Histocompatibility Antigens
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Models, Biological
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Proto-Oncogene Proteins*
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RNA / metabolism
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RNA, Long Noncoding
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RNA, Untranslated / genetics
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RNA, Untranslated / metabolism
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Repressor Proteins*
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Stem Cells / physiology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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X Chromosome / metabolism*
Substances
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A Kinase Anchor Proteins
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AKAP13 protein, human
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Adaptor Proteins, Signal Transducing
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Chromatin
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Enzyme Inhibitors
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Histones
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Mecp2 protein, mouse
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Methyl-CpG-Binding Protein 2
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Minor Histocompatibility Antigens
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Oncogene Proteins
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Proto-Oncogene Proteins
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RNA, Long Noncoding
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RNA, Untranslated
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Repressor Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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XIST non-coding RNA
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Cyclin-Dependent Kinase Inhibitor p27
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RNA