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| Status |
Public on May 05, 2017 |
| Title |
Impact of cytosine methylation on DNA binding specificities of human transcription factors. |
| Organism |
synthetic construct |
| Experiment type |
Other
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| Summary |
The majority of CpG dinucleotides in the human genome are methylated at cytosine bases. The methylation is heritable across cell divisions, and contributes to the epigenetic memory that maintains the differentiated state of distinct cell types. Active gene regulatory elements are generally undermethylated relative to their flanking regions, and the undermethylation is thought to be important for their activity. Consistently with this model, the binding of some transcription factors (TFs) is diminished by methylation of their target sequences. By systematic analysis of 542 human TFs using methylation sensitive SELEX, we find here that a large number of TFs also prefer to bind to CpG methylated sequences. Most of these represent the extended homeodomain family. Structural analysis of HOXB13, CDX1, CDX2 and LHX4 revealed that the specificity of homeodomain proteins towards methylcytosine depends on amino-acids that form direct hydrophobic interactions with the 5-methyl group of methylcytosine. Our results provide a systematic examination of the effect of an epigenetic DNA modification on human TF binding specificity, and reveal that many developmentally important homeodomain proteins display strong preference for binding to mCpG containing sequences.
Genome-scale analysis reveals that binding of most transcription factors is affected by CpG methylation, and that many developmentally important homeodomain TFs directly recognize the 5-methyl group of methylcytosine.
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| Overall design |
Protein binding microarray (PBM) experiments were performed for a set of 8 Human transcription factors: LHX9, NKX2.5, DLX3, POU5F1, MAX, NFATC2, CUX1 and CUX2, for their ability to bind 5-methylcytosine in CG sequence context. Briefly, the PBMs involved binding GST-tagged DNA-binding domains of the human TFs to double-stranded methylated or unmethylated 44K Agilent microarrays. These microarrays are based on DeBruijn sequence design. Details of the PBM protocol are described in Mann et al., Genome Res. 2013 Jun;23(6):988-97.
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| Contributor(s) |
Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, Das PK, Kivioja T, Dave K, Zhong F, Nitta KR, Taipale M, Popov A, Ginno P, Domcke S, Yan J, Schübeler D, Vinson C, Taipale J |
| Citation(s) |
28473536 |
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| Submission date |
Feb 07, 2017 |
| Last update date |
Aug 07, 2017 |
| Contact name |
Syed Khund Sayeed |
| E-mail(s) |
khundsayeed@hotmail.com
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| Phone |
+917995232864
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| Organization name |
National Cancer Institute
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| Department |
Center for Cancer Research
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| Lab |
Laboratory of Metabolism
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| Street address |
Building 37, NIH
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| City |
BETHESDA |
| State/province |
maryland |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
| GPL11260 |
Agilent custom ME and HK design array [8mer] |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA371642 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE94634_RAW.tar |
89.8 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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