Loss of human ribosomal gene CpG methylation enhances cryptic RNA polymerase II transcription and disrupts ribosomal RNA processing

Thérèse Gagnon-Kugler; Frédéric Langlois; Victor Stefanovsky; Frédéric Lessard; Tom Moss

doi:10.1016/j.molcel.2009.07.008

Loss of human ribosomal gene CpG methylation enhances cryptic RNA polymerase II transcription and disrupts ribosomal RNA processing

Mol Cell. 2009 Aug 28;35(4):414-25. doi: 10.1016/j.molcel.2009.07.008.

Authors

Thérèse Gagnon-Kugler¹, Frédéric Langlois, Victor Stefanovsky, Frédéric Lessard, Tom Moss

Affiliation

¹ Cancer Research Centre, CHUQ-HDQ Research Centre, Pavillon St. Patrick, 9 Rue McMahon, Québec, QC G1R 3S3, Canada.

PMID: 19716787
DOI: 10.1016/j.molcel.2009.07.008

Abstract

Epigenetic methyl-CpG silencing of the ribosomal RNA (rRNA) genes is thought to downregulate rRNA synthesis in mammals. In contrast, we now show that CpG methylation in fact positively influences rRNA synthesis and processing. Human HCT116 cells, inactivated for DNMT1 and DNMT3b or treated with aza-dC, lack CpG methylation and reactivate a large fraction of normally silent rRNA genes. Unexpectedly, these cells display reduced rRNA synthesis and processing and accumulate unprocessed 45S rRNA. Reactivation of the rRNA genes is associated with their cryptic transcription by RNA polymerase II. Ectopic expression of cryptic rRNA gene transcripts recapitulates the defects associated with loss of CpG methylation. The data demonstrate that rRNA gene silencing prevents cryptic RNA polymerase II transcription of these genes. Lack of silencing leads to the partial disruption of rRNA synthesis and rRNA processing, providing an explanation for the cytotoxic effects of loss of CpG methylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Azacitidine / analogs & derivatives
Azacitidine / pharmacology
Cell Nucleolus / drug effects
Cell Nucleolus / metabolism*
Cell Nucleolus / pathology
Cell Proliferation
Cell Survival
CpG Islands*
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA (Cytosine-5-)-Methyltransferases / metabolism
DNA Methylation* / drug effects
DNA Methyltransferase 3B
DNA, Ribosomal / metabolism*
Decitabine
Enzyme Inhibitors / pharmacology
HCT116 Cells
Humans
Kinetics
RNA Polymerase II / genetics
RNA Polymerase II / metabolism*
RNA Processing, Post-Transcriptional
RNA Stability
RNA, Ribosomal / metabolism*
Transcription, Genetic* / drug effects

Substances

DNA, Ribosomal
Enzyme Inhibitors
RNA, Ribosomal
RNA, ribosomal, 45S
Decitabine
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNMT1 protein, human
RNA Polymerase II
Azacitidine

Associated data

GEO/GSE17042