Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b.

Abstract:

:The Ets transcription factor PU.1 is a hematopoietic master regulator essential for the development of myeloid and B-cell lineages. As we previously reported, PU.1 sometimes represses transcription on forming a complex with mSin3A-histone deacetyl transferase-MeCP2. Here, we show an interaction between PU.1 and DNA methyltransferases, DNA methyltransferase (Dnmt)3a and Dnmt3b (Dnmt3s). Glutathione-S-transferase pulldown assay revealed that PU.1 directly interacted with the ATRX domain of Dnmt3s through the ETS domain. Dnmt3s repressed the transcriptional activity of PU.1 on a reporter construct with trimerized PU.1-binding sites. The repression was recovered by addition of 5-aza-deoxycitidine, a DNA methyltransferase inhibitor, but not trichostatin A, a histone deacetylase inhibitor. Bisulfite sequence analysis revealed that several CpG sites in the promoter region neighboring the PU.1-binding sites were methylated when Dnmt3s were coexpressed with PU.1. We also showed that the CpG sites in the p16(INK4A) promoter were methylated by overexpression of PU.1 in NIH3T3 cells, accompanied by a downregulation of p16(INK4A) gene expression. These results suggest that PU.1 may downregulate its target genes through an epigenetic modification such as DNA methylation.

journal_name

Oncogene

journal_title

Oncogene

authors

Suzuki M,Yamada T,Kihara-Negishi F,Sakurai T,Hara E,Tenen DG,Hozumi N,Oikawa T

doi

10.1038/sj.onc.1209272

subject

Has Abstract

pub_date

2006-04-20 00:00:00

pages

2477-88

issue

17

eissn

0950-9232

issn

1476-5594

pii

1209272

journal_volume

25

pub_type

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