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Series GSE67867 Query DataSets for GSE67867
Status Public on Dec 16, 2015
Title Competition between DNA methylation and transcription factors determines binding of NRF1
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Summary Eukaryotic transcription factors (TFs) are key determinants of gene activity, yet they bind only a fraction of their corresponding DNA sequence motifs in any given cell type. Chromatin has the potential to restrict accessibility of binding sites; however, in which context chromatin states are instructive for TF binding remains mainly unknown. To explore the contribution of DNA methylation to constrained TF binding, we mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for TF motifs containing CpGs, especially for those of NRF1. In fact, the TF NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA-methylationsensitive TFs relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighbouring motifs in cis or of a TF in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and TFs in vivo reveals a case of cooperativity between TFs that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions.
Overall design DNase-seq (2 replicates) in mouse embryonic stem cells with (WT) and without DNA methylation (DNMT TKO). RNA-seq (3 replicates) in WT and DNMT TKO cells and in DNMT TKO cells after treatment with control siRNA or siRNA targeting Nrf1. H3K27ac ChIP-seq (2 replicates) in WT and DNMT TKO cells. NRF1 ChIP-seq (2 replicates) in WT and DNMT TKO cells, in WT upon culture in different conditions (adaptation to 2i and back to serum), upon transient overexpression of NRF1 and after differentiation into neuronal progenitor cells (NP). Whole-genome bisulfite sequencing in DNMT TKO cells and in WT upon culture in different conditions (adaptation to 2i and back to serum). NRF1 ChIP-seq (2 replicates) in human HMEC and HCC1954 cells.
Contributor(s) Domcke S, Bardet AF, Schübeler D
Citation(s) 26675734
Submission date Apr 14, 2015
Last update date May 15, 2019
Contact name Anais Flore Bardet
Organization name IGBMC
Street address 1 rue Laurent Fries
City Illkirch
ZIP/Postal code 67404
Country France
Platforms (2)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (48)
GSM1657364 DNASE_WT_1
GSM1657365 DNASE_WT_2
GSM1657366 DNASE_TKO_1
BioProject PRJNA281090
SRA SRP057157

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Supplementary file Size Download File type/resource
GSE67867_RAW.tar 12.4 Gb (http)(custom) TAR (of BW, TSV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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