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PMID:19786833

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Citation

Hervouet, E, Vallette, FM and Cartron, PF (2009) Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics 4:487-99

Abstract

Epigenetic gene inactivation in mammalian cells involves many silencing mechanisms. One of these mechanisms is the transcriptional repression by targeted promoter hypermethylation. However, the molecular mechanisms involved in the site-specific DNA (hyper)methylation are not fully elucidate. By using the Dnmt3a/c-myc interaction as an example, we here showed that this interaction promotes the site-specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Indeed, the invalidation of c-myc reveals that c-myc allows the Dnmt3a recruitment on c-myc box of c-myc-regulated genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. Indeed, our work indicates that Dnmt3a and Dnmt3b have consensus sequences to methylate DNA (T/A/C)(A/T)(T/G/A)CG(T/G/C)G(G/C/A) and (A/C)(C/G/A)(A/G)CGT(C/G)(A/G). Thus, the low specificity of these sequences (consensual for 162 and 48 possibilities, respectively) does not support the idea of targeted DNA methylation. By monitoring transcription factor arrays spotted with 103 transcription factors, we next identified 42 transcription factors interacting with Dnmt3a and Dnmt3b (such as CREB and FOS), 27 transcription factors interacting with Dnmt3a (such as AP2alpha and p53), 10 transcription factors interacting with Dnmt3b (such as SP1 and SP4) and 24 transcription factors devoid of direct interaction with Dnm3a and Dnmt3b (such as C/EBPalpha and NFkappaB-p65). Thus, The description of direct interaction between Dnmt3a and/or Dnmt3b and transcription factors provides rational molecular explanation to the mechanisms of targeted DNA (hyper)methylation, and to the mechanisms by which transcription factors repress genes expression.

Links

PubMed

Keywords

Base Sequence; Cell Line, Tumor; Cyclin D1/genetics; Cyclin D1/metabolism; Cyclin-Dependent Kinase Inhibitor p21/genetics; Cyclin-Dependent Kinase Inhibitor p21/metabolism; DNA (Cytosine-5-)-Methyltransferases/genetics; DNA (Cytosine-5-)-Methyltransferases/metabolism; DNA Methylation; Gene Expression Regulation, Neoplastic; Glycoproteins/genetics; Glycoproteins/metabolism; Humans; Insect Proteins/genetics; Insect Proteins/metabolism; Protein Binding; Proto-Oncogene Proteins c-myc/genetics; Proto-Oncogene Proteins c-myc/metabolism; RNA, Small Interfering/genetics; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MYC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y6K1

F

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P24385)

Seeded From UniProt

complete

HUMAN:MYC

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • occurs_at:(SO:0000167)

Seeded From UniProt

complete

HUMAN:MYC

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • has_input:(UniProtKB:P24385)
  • occurs_at:(SO:0005836)

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:1905643: positive regulation of DNA methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • part_of:(GO:0000122)
  • has_input:(UniProtKB:P24385)
  • occurs_at:(SO:0005836)

Seeded From UniProt

complete

HUMAN:DNM3A

enables

GO:0003886: DNA (cytosine-5-)-methyltransferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DNM3A

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P24385)

Seeded From UniProt

complete

HUMAN:DNM3A

involved_in

GO:0006306: DNA methylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P24385)
  • occurs_at:(SO:0005836)

Seeded From UniProt

complete

HUMAN:DNM3A

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0000167)

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:1905643: positive regulation of DNA methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • part_of:(GO:0000122)
  • has_direct_input:(UniProtKB:P24385)
  • occurs_at:(SO:0005836)

Seeded From UniProt

complete

HUMAN:MYC

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • has_direct_input:(UniProtKB:P24385)
  • occurs_at:(SO:0005836)

Seeded From UniProt

complete

HUMAN:MYC

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

has_direct_input:(UniProtKB:P24385)

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

regulates_transcription_of:(ENSEMBL:ENSG00000110092)

Seeded From UniProt

complete

HUMAN:DNM3A

enables

GO:0003714: transcription corepressor activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DNM3A

enables

GO:0003886: DNA (cytosine-5-)-methyltransferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • part_of:(GO:0000122)
  • regulates_transcription_of:(ENSEMBL:ENSG00000110092)

Seeded From UniProt

complete

HUMAN:DNM3A

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P01106

F

Seeded From UniProt

complete

HUMAN:DNM3A

involved_in

GO:0006306: DNA methylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_direct_input:(ENSEMBL:ENSG00000110092)
  • occurs_at:(SO:0005836)

Seeded From UniProt

complete

HUMAN:DNM3A

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

has_direct_input:(ENSEMBL:ENSG00000110092)

Seeded From UniProt

complete

HUMAN:DNM3A

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

regulates_transcription_of:(ENSEMBL:ENSG00000110092)

Seeded From UniProt

complete

Notes

See also

References

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