DNA methylation plays an important role in promoter choice and protein production at the mouse Dnmt3L locus

Alan M. O'Doherty, Charlotte E. Rutledge, Shun Sato, Avinash Thakur, Diane Lees Murdock, Kenichiro Hata, Colum Walsh

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Abstract

The DNA methyltransferase 3-like (Dnmt3L) protein is a crucial cofactor in the germ line for the de novo methyltransferase Dnmt3a, which establishes imprints and represses transposable elements. We have previously shown that Dnmt3L transcription is regulated via three different promoters in mice, producing transcripts we term Dnmt3L(s) (stem cell), Dnmt3L(o) (oocyte) and Dnmt3L(at) (adult testis). Here we show that both Dnmt3L(s) and Dnmt3L(o) produce full-length proteins but that the Dnmt3L(at) transcripts are not translated. Although not a canonical CpG island, the Dnmt3L(s) promoter is silenced by methylation during somatic differentiation in parallel with germ-cell-specific genes. During oocyte growth, Dnmt3L(s) also becomes heavily methylated and silenced and this requires its own gene product, since there is complete loss of methylation and derepression of transcription from this promoter in oocytes derived from Dnmt3L(-/-) mice. Methylation of the Dnmt3L(s) promoter is established prior to the completion of imprinting and explains the requirement in mouse oocytes for the Dnmt3L(o) promoter, located in an intron of the neighboring unmethylated Aire gene. Overall these results give insight into how and why promoter switching at the mouse Dnmt3L locus occurs and provide one of the first examples of a non-imprinted locus where methylation plays a role in promoter choice. The derepression of the Dnmt3L(s) promoter in the knockout oocytes also suggests that other non-imprinted loci may be dysregulated in these cells and contribute to the phenotype of the resultant mice. (C) 2011 Elsevier Inc. All rights reserved.
LanguageEnglish
Pages411-420
JournalDevelopmental Biology
Volume356
Issue number2
DOIs
Publication statusPublished - Aug 2011

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Methyltransferases
DNA Methylation
DNA
Proteins
Oocytes
Methylation
Germ Cells
Protein Methyltransferases
Genes
CpG Islands
DNA Transposable Elements
Introns
Testis

Cite this

O'Doherty, Alan M. ; Rutledge, Charlotte E. ; Sato, Shun ; Thakur, Avinash ; Lees Murdock, Diane ; Hata, Kenichiro ; Walsh, Colum. / DNA methylation plays an important role in promoter choice and protein production at the mouse Dnmt3L locus. In: Developmental Biology. 2011 ; Vol. 356, No. 2. pp. 411-420.
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abstract = "The DNA methyltransferase 3-like (Dnmt3L) protein is a crucial cofactor in the germ line for the de novo methyltransferase Dnmt3a, which establishes imprints and represses transposable elements. We have previously shown that Dnmt3L transcription is regulated via three different promoters in mice, producing transcripts we term Dnmt3L(s) (stem cell), Dnmt3L(o) (oocyte) and Dnmt3L(at) (adult testis). Here we show that both Dnmt3L(s) and Dnmt3L(o) produce full-length proteins but that the Dnmt3L(at) transcripts are not translated. Although not a canonical CpG island, the Dnmt3L(s) promoter is silenced by methylation during somatic differentiation in parallel with germ-cell-specific genes. During oocyte growth, Dnmt3L(s) also becomes heavily methylated and silenced and this requires its own gene product, since there is complete loss of methylation and derepression of transcription from this promoter in oocytes derived from Dnmt3L(-/-) mice. Methylation of the Dnmt3L(s) promoter is established prior to the completion of imprinting and explains the requirement in mouse oocytes for the Dnmt3L(o) promoter, located in an intron of the neighboring unmethylated Aire gene. Overall these results give insight into how and why promoter switching at the mouse Dnmt3L locus occurs and provide one of the first examples of a non-imprinted locus where methylation plays a role in promoter choice. The derepression of the Dnmt3L(s) promoter in the knockout oocytes also suggests that other non-imprinted loci may be dysregulated in these cells and contribute to the phenotype of the resultant mice. (C) 2011 Elsevier Inc. All rights reserved.",
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DNA methylation plays an important role in promoter choice and protein production at the mouse Dnmt3L locus. / O'Doherty, Alan M.; Rutledge, Charlotte E.; Sato, Shun; Thakur, Avinash; Lees Murdock, Diane; Hata, Kenichiro; Walsh, Colum.

In: Developmental Biology, Vol. 356, No. 2, 08.2011, p. 411-420.

Research output: Contribution to journalArticle

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AB - The DNA methyltransferase 3-like (Dnmt3L) protein is a crucial cofactor in the germ line for the de novo methyltransferase Dnmt3a, which establishes imprints and represses transposable elements. We have previously shown that Dnmt3L transcription is regulated via three different promoters in mice, producing transcripts we term Dnmt3L(s) (stem cell), Dnmt3L(o) (oocyte) and Dnmt3L(at) (adult testis). Here we show that both Dnmt3L(s) and Dnmt3L(o) produce full-length proteins but that the Dnmt3L(at) transcripts are not translated. Although not a canonical CpG island, the Dnmt3L(s) promoter is silenced by methylation during somatic differentiation in parallel with germ-cell-specific genes. During oocyte growth, Dnmt3L(s) also becomes heavily methylated and silenced and this requires its own gene product, since there is complete loss of methylation and derepression of transcription from this promoter in oocytes derived from Dnmt3L(-/-) mice. Methylation of the Dnmt3L(s) promoter is established prior to the completion of imprinting and explains the requirement in mouse oocytes for the Dnmt3L(o) promoter, located in an intron of the neighboring unmethylated Aire gene. Overall these results give insight into how and why promoter switching at the mouse Dnmt3L locus occurs and provide one of the first examples of a non-imprinted locus where methylation plays a role in promoter choice. The derepression of the Dnmt3L(s) promoter in the knockout oocytes also suggests that other non-imprinted loci may be dysregulated in these cells and contribute to the phenotype of the resultant mice. (C) 2011 Elsevier Inc. All rights reserved.

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