The DNA methyltransferase inhibitor 5-azacytidine specifically alters the expression of helix-loop-helix proteins Id1, Id2 and Id3 during neuronal differentiation.
In mammals, cytosine methylation is important for the regulation of gene expression and chromatin structure. Recently, we have found evidence indicating that the maintained DNA methyltransferase activity is critical for neuronal cell differentiation. In the present study, we have investigated the effect of the DNA methyltransferase inhibitor 5-azacytidine on gene regulation during nerve growth factor (NGF)-induced neuronal differentiation of PC12 cells. Expression of the helix-loop-helix proteins Id1, Id2 and Id3 was specifically reduced by NGF and this effect was blocked in 5-azacytidine-treated cells, concomitant with the inhibition of NGF-induced neuronal differentiation. Nuclear run-on and Id2 promoter analyses further demonstrated that the decreased transcription of Id proteins is at least in part dependent on the DNA methyltransferase activity. These findings indicate that Id proteins are downstream targets of the NGF transduction pathway. Moreover, these results suggest that therapeutic strategies using 5-azacytidine against certain types of tumors should be reconsidered because of the possible deleterious effects on neuronal cell function.
Persengiev
S P
SP
Neurobiology Group, Worcester Foundation for Biomedical Research, Shrewsbury, MA 01545, USA.
Kilpatrick
D L
DL
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D004247:DNA / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018257:Helix-Loop-Helix Motifs / Q000187:drug effects* / Q000235:genetics*; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D008780:Methyltransferases / Q000187:drug effects; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D012097:Repressor Proteins; D014157:Transcription Factors / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; C497454:ID1 protein, rat; C497451:Id2 protein, rat; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C075640:ID3 protein, human; D004247:DNA; D008780:Methyltransferases; D001374:Azacitidine