Abstract
Histone monoubiquitylation is implicated in critical regulatory processes. We explored the roles of histone H2B ubiquitylation in human cells by reducing the expression of hBRE1/RNF20, the major H2B-specific E3 ubiquitin ligase. While H2B ubiquitylation is broadly associated with transcribed genes, only a subset of genes was transcriptionally affected by RNF20 depletion and abrogation of H2B ubiquitylation. Gene expression dependent on RNF20 includes histones H2A and H2B and the p53 tumor suppressor. In contrast, RNF20 suppresses the expression of several proto-oncogenes, which reside preferentially in closed chromatin and are modestly transcribed despite bearing marks usually associated with high transcription rates. Remarkably, RNF20 depletion augmented the transcriptional effects of epidermal growth factor (EGF), increased cell migration, and elicited transformation and tumorigenesis. Furthermore, frequent RNF20 promoter hypermethylation was observed in tumors. RNF20 may thus be a putative tumor suppressor, acting through selective regulation of a distinct subset of genes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Cell Movement
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Cell Transformation, Neoplastic
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Chromatin / genetics
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Chromatin / metabolism
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DNA Methylation
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DNA, Neoplasm / chemistry
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DNA, Neoplasm / genetics
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DNA, Neoplasm / metabolism
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Epidermal Growth Factor / pharmacology
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Female
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Gene Expression Regulation / drug effects
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HeLa Cells
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Histones / chemistry
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Histones / metabolism*
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Humans
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Mice
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Mice, Nude
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Promoter Regions, Genetic
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RNA Polymerase II / metabolism
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RNA, Small Interfering / genetics
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Suppression, Genetic
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / antagonists & inhibitors
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
Substances
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Chromatin
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DNA, Neoplasm
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Histones
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RNA, Small Interfering
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TP53 protein, human
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Epidermal Growth Factor
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RNF20 protein, human
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RNF20 protein, mouse
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Ubiquitin-Protein Ligases
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RNA Polymerase II