DNA methylation and chromatin – unraveling the tangled web

Robertson, Keith D.

doi:10.1038/sj.onc.1205609

Cited by 419 publications

(317 citation statements)

References 134 publications

Supporting

Mentioning

306

Contrasting

Unclassified

Order By: Relevance

“…DNMT1 is generally considered to be a maintenance methylase, although it also has de novo methylase activity (Bestor, 2000;Robertson, 2002). Both DNMT3A and DNMT3B catalyse de novo methylation of DNA sequences (Li, 2002).…”

Section: Introductionmentioning

confidence: 99%

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

et al. 2007

View full text Add to dashboard Cite

Cancer cells display an altered distribution of DNA methylation relative to normal cells. Certain tumor suppressor gene promoters are hypermethylated and transcriptionally inactivated, whereas repetitive DNA is hypomethylated and transcriptionally active. Little is understood about how the abnormal DNA methylation patterns of cancer cells are established and maintained. Here, we identify over 20 DNMT3B transcripts from many cancer cell lines and primary acute leukemia cells that contain aberrant splicing at the 5 0 end of the gene, encoding truncated proteins lacking the C-terminal catalytic domain. Many of these aberrant transcripts retain intron sequences. Although the aberrant transcripts represent a minority of the DNMT3B transcripts present, Western blot analysis demonstrates truncated DNMT3B isoforms in the nuclear protein extracts of cancer cells. To test if expression of a truncated DNMT3B protein could alter the DNA methylation patterns within cells, we expressed DNMT3B7, the most frequently expressed aberrant transcript, in 293 cells. DNMT3B7-expressing 293 cells have altered gene expression as identified by microarray analysis. Some of these changes in gene expression correlate with altered DNA methylation of corresponding CpG islands. These results suggest that truncated DNMT3B proteins could play a role in the abnormal distribution of DNA methylation found in cancer cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

et al. 2007

View full text Add to dashboard Cite

show abstract

“…In addition, chromatin at inactive promoters is generally hypoacetylated by histone deacetylases (HDAC) that can be inhibited by HDAC inhibitors such as Trichostatin A (TSA). Because DNMT1 has been found to interact physically with HDACs, DNA-methylation and histone deacetylation may function through a common mechanistic pathway to repress transcription (Rountree et al, 2000;Dobosy and Selker, 2001;Robertson, 2002). The use of both TSA and AZA has synergistic effects in activating epigenetically silenced genes (Cameron et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells

et al. 2008

View full text Add to dashboard Cite

In breast cancer, approximately one-third of tumors express neither the estrogen receptor (ERa) nor estrogen-regulated genes such as the progesterone receptor gene (PR). Our study provides new insights into the mechanism allowing hormone-activated expression of ERa target genes silenced in ERa-negative mammary tumor cells. In cell lines derived from ERa-negative MDA-MB231 cells, stable expression of different levels of ERa from a transgene did not result in transcription of PR. A quantitative comparative analysis demonstrates that inhibiting DNA methyltransferases using 5-aza-2 0 -deoxycytidine or specific disruption of DNMT1 by small interfering RNAs and treatment with the histone-deacetylase inhibitor trichostatin A enabled ERa-mediated hormone-dependent expression of endogenous PR. We show that demethylation of a CpG island located in the first exon of PR was a prerequisite for ERa binding to these regulatory sequences. Although not a general requirement, DNA demethylation is also necessary for derepression of a subset of ERa target genes involved in tumorigenesis. PR transcription did not subsist 4 days after removal of the DNA methyltransferase blocking agents, suggesting that hormone-induced expression of ERa target genes in ERa-negative tumor cells is transient. Our observations support a model where an epigenetic mark confers stable silencing by precluding ERa access to promoters.

show abstract

“…It is documented that the methylation of CpG islands is associated with changes in chromatin structure and the repression of gene transcription (Robertson, 2002). Many studies have also revealed that aberrant DNA methylation in tumor suppressor genes such as p16/INK4a, p19/ARF and p21/WAF1 are early events in the process of tumorigenesis (Robertson, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

DNA methylation and chromatin – unraveling the tangled web

Cited by 419 publications

References 134 publications

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells

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

Contact Info

Product

Resources

About