BioGPS Featured Article – Constrained transcription factor spacing is prevalent and important for transcriptional control of mouse blood cells

BioGPS has become the valuable resource that it is because of the contributions from our wonderful user community. Thank you for contributing plugins, suggestions, and ideas–all of which have improved BioGPS for everyone. In order to celebrate the contributions of BioGPS users to the scientific research community, this series will feature publications and articles generated by BioGPS users. We sincerely hope you will join us in celebrating the fascinating work that YOU do.

This week, we will feature an article by the Göttgens lab at the Cambridge Institute for Medical Research: Constrained transcription factor spacing is prevalent and important for transcriptional control of mouse blood cells by Felicia SL Ng, Judith Schütte, David Ruau, Evangelia Diamanti, Rebecca Hannah, Sarah J. Kinston, and Berthold Göttgens.

Felicia Ng, the first author of this paper, kindly answered our inquiries for this series.

1. Who is the team behind the work that was published in Constrained transcription factor spacing is prevalent and important for transcriptional control of mouse blood cells?.
   The authors are members of the Göttgens lab led by Prof Berthold Göttgens and we study the transcriptional control of normal and leukemic blood/stem progenitor cells. More details about our research can be found here – http://hscl.cimr.cam.ac.uk/research.html.

 

2. What inspired the work published in Constrained transcription factor spacing is prevalent and important for transcriptional control of mouse blood cells?
   Transcription factors are important regulators of cell-type-specific gene expression. However, the precise arrangement of TFs when bound to DNA on enhancer regions is still unclear. Various models of enhancer activity have been suggested including the ‘enhanceosome’ model which requires precise spacing between TFs, and the ‘TF collective’ model which does not have this requirement. It was also unclear which model is prevalent in the transcriptional control of mouse blood cells.
   Widespread up-take of next generation sequencing technology by the scientific community has also provided access to large numbers of public ChIP-seq data, especially in mouse blood cells. This collection of data provides a unique opportunity to study the global impact of a large number of transcription factors across all major blood cell types. HAEMCODE (Ruau et al, 2013 Nat Methods) is one such initiative that compiled and uniformly processed all public ChIP-seq datasets relevant to mouse blood cells.

 

3. Please provide a brief summary of the findings reported in your article, Constrained transcription factor spacing is prevalent and important for transcriptional control of mouse blood cells.
   • Utilizing a compendium of 289 mouse haematopoietic TF ChIP-seq datasets, we demonstrated that haematopoietic-related motif-pairs commonly occur with highly conserved constrained spacing and orientation between motifs.
   • Motif clustering revealed specific associations for both heterotypic and homotypic motif-pairs with particular haematopoietic cell types.
   • We also showed that disrupting the spacing between motif-pairs significantly affects transcriptional activity in a well-known motif-pair – E-box and GATA, and in two previously unknown motif-pairs with constrained spacing – Ets and Homeobox as well as Ets and E-box.
   • We provided evidence for widespread sequence-specific TF pair interaction with DNA that conforms to the ‘enhanceosome’ model, and furthermore identify associations between specific haematopoietic cell-types and motif-pairs.

 

4. How did the team learn about BioGPS?
   We came across the publication by Wu et al. (2009) in Genome Biology.

 

5. How did your team utilize BioGPS in this research?
   We downloaded the raw microarray data from NCBI GEO and processed the data using the ‘gcrma’ R package in order to identify genes that are expressed in any of the blood-related cell types. This allowed us to identify candidate genes that contain motif-pairs of interest in their promoters.

 

6. What are some future directions for the team behind this research?
   In this paper, we also observed cell-type-specific spacing preferences and we hope to explore this further to understand the impact of preferential spacing on the transcriptional control of distinct blood cell types.

 

Thanks again to Felicia Ng for taking the time to answer our questions. Click here to read their fascinating article. Have a look because these awesome researchers have made their compelling research open access–so you can read the whole exciting article for free!

Used BioGPS and cited it in your publication? Let us know! We would love to feature YOUR work, no matter how long ago it was published. BioGPS Featured Article Series only started recently, but we know your contributions to science is ongoing.