The healthy development of a living cell requires precise spatial-temporal gene expression. The code that dictates when and where genes are expressed is stored in a pattern of specific sequence motifs, which can be recognised by transcription factors. Understanding the interaction between these DNA sequence motifs and transcription factors will help to elucidate how genomic sequences build transcriptional control networks. However, the DNA-binding specificities of ~1400 human transcription factors are largely unknown. The in vivo DNA-binding events of transcription factors involve great subtlety, because most transcription factors recognise degenerate sequence motifs and related transcription factors often prefer similar or even identical sequences. Forkhead transcription factors exemplify these challenges. To understand how members within the Forkhead transcription factor family gain their binding and functional specificities, we used chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) to interrogate the genome-wide chromatin binding events of three Forkhead transcription factors: FOXM1, FOXO3 and FOXK2. We find that FOXM1 specifically binds to the promoters of a large array of genes whose activities peak at the G2 and M phases of the cell cycle. The canonical Forkhead consensus GTAAACA is not enriched within the FOXM1 cistrome. It gains its own specific binding events and biological functions by interacting and cooperating with the MMB complex. FOXO3 and FOXK2 are recruited to chromatin by the canonical Forkhead consensus GTAAACA, and they bind both shared and specific regions in the genome. FOXO3 mostly binds to the regions which are also bound by FOXK2, but no competitive or assisted binding between FOXO3 and FOXK2 is detected within those regions. Overall, these results help explain how individual members of the Forkhead transcription factor family gain binding specificity within the genome yet raises new questions of how functional specificity is achieved by other family members.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:677718 |
| Date | January 2012 |
| Creators | Chen, Xi |
| Contributors | Sharrocks, Andrew ; Whitmarsh, Alan |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/the-dnabinding-specificity-of-forkhead-transcription-factors(bc02fd29-30d0-47da-9b4f-448687504463).html |
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