Role of DNA Methylation in Stable Gene Repression

Abstract

A large fraction of the animal genome is maintained in a transcriptionally repressed state throughout development. By generating viable Dnmt1-/- mouse cells we have been able to study the effect of DNA methylation on both gene expression and chromatin structure. Our results confirm that the underlying methylation pattern has a profound effect on histone acetylation and is the major effector of me-H3(K4) in the animal genome. We demonstrate that many methylated genes are subject to additional repression mechanisms that also impact on histone acetylation, and the data suggest that late replication timing may play an important role in this process. A large fraction of the animal genome is maintained in a transcriptionally repressed state throughout development. By generating viable Dnmt1-/- mouse cells we have been able to study the effect of DNA methylation on both gene expression and chromatin structure. Our results confirm that the underlying methylation pattern has a profound effect on histone acetylation and is the major effector of me-H3(K4) in the animal genome. We demonstrate that many methylated genes are subject to additional repression mechanisms that also impact on histone acetylation, and the data suggest that late replication timing may play an important role in this process. The transcription of many genes in the animal genome is stably repressed. These include tissue-specific genes that are constitutively silenced in almost all cell types and only activated in their tissue of expression, as well as embryonic genes that are turned off during early development and then remain repressed in most cell types. These observations strongly suggest the existence of basic mechanisms capable of maintaining repression through the repeated cell divisions that take place during development.One of the main mechanisms maintaining gene repression is DNA The animal genome is a pattern of methylation in most gene are methylated in genes are constitutively is the of a of methylation and is then maintained throughout genes in their tissue of of this pattern has been that DNA methylation may play a role in the repression of transcription is strongly in tissue and in that that methylated DNA is repressed and in a chromatin through a that is that methylation gene expression that all methylated genes in the genome are stably repressed this well mechanisms may also take in this process. are stably silenced of that are constitutively to gene These the transcription chromatin through histone that may gene repression is DNA replication timing The genome to of is to in a during genes are in that constitutively many tissue-specific genes late in most cell types are to early in their tissue of suggest that the of replication gene and These that DNA in early the that late in this is repeated in cell late replication timing maintaining gene the role of DNA methylation the of additional repression we have DNA that have almost all this we a large of genes in the mouse their DNA methylation expression histone and replication timing has to DNA methylation basic repression mechanisms to of gene cell mouse cells embryonic mouse The cell the and on in and the histone A transcription a that the cell in cells the of to the and are the is the and to the and in a of the in the of and to in to and on and state gene of and the of to that of cells the of The results that that this has a of of of the results on the and data chromatin and and chromatin and to we of the in this of the fraction a of the on of in the of and to take the of DNA in the and this as a that in to all of the genes chromatin to that are gene 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histone is the that histone and as a of their underlying as the histone The transcription of many genes in the animal genome is stably repressed. These include tissue-specific genes that are constitutively silenced in almost all cell types and only activated in their tissue of expression, as well as embryonic genes that are turned off during early development and then remain repressed in most cell types. These observations strongly suggest the existence of basic mechanisms capable of maintaining repression through the repeated cell divisions that take place during development. of the main mechanisms maintaining gene repression is DNA The animal genome is a pattern of methylation in most gene are methylated in genes are constitutively is the of a of methylation and is then maintained throughout genes in their tissue of of this pattern has been that DNA methylation may play a role in the repression of transcription is strongly in tissue and in that that methylated DNA is repressed and in a chromatin through a that is that methylation gene expression that all methylated genes in the genome are stably repressed this well mechanisms may also take in this process. are stably silenced of that are constitutively to gene These the transcription chromatin through histone that may gene repression is DNA replication timing The genome to of is to in a during genes are in that constitutively many 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