General transcription factor binding at CpG islands in normal cells correlates with resistance to de novo DNA methylation in cancer cells.
Aberrant DNA methylation at CpG islands is thought to contribute to cancer initiation and progression, but mechanisms that establish and maintain DNA methylation status during tumorigenesis or normal development remain poorly understood. In this study, we used methyl-CpG immunoprecipitation to generate comparative DNA methylation profiles of healthy and malignant cells (acute leukemia and colorectal carcinoma) for human CpG islands across the genome. While searching for sequence patterns that characterize DNA methylation states, we discovered several nonredundant sequences in CpG islands that were resistant to aberrant de novo methylation in cancer and that resembled consensus binding sites for general transcription factors (TF). Comparing methylation profiles with global CpG island binding data for specific protein 1, nuclear respiratory factor 1, and yin-yang 1 revealed that their DNA binding activity in normal blood cells correlated strictly with an absence of de novo methylation in cancer. In addition, global evidence showed that binding of any of these TFs to their consensus motif depended on their co-occurrence with neighboring consensus motifs. In summary, our results had two major implications. First, they pointed to a major role for cooperative binding of TFs in maintaining the unmethylated status of CpG islands in health and disease. Second, our results suggest that the majority of de novo methylated CpG islands are characterized by the lack of sequence motif combinations and the absence of activating TF binding.
Department of Hematology and Institute of Pathology, University Hospital Regensburg, D-93042 Regensburg, Germany.
Claudia
C
Gebhard
Chris
C
Benner
Mathias
M
Ehrich
Lucia
L
Schwarzfischer
Elmar
E
Schilling
Maja
M
Klug
Wolfgang
W
Dietmaier
Christian
C
Thiede
Ernst
E
Holler
Reinhard
R
Andreesen
Michael
M
Rehli
D000328:Adult; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007938:Leukemia / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D055815:Young Adult
D014157:Transcription Factors