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The transcriptional programme controlled by Runx1 during early embryonic blood development.

ABSTRACT: Transcription factors have long been recognised as powerful regulators of mammalian development yet it is largely unknown how individual key regulators operate within wider regulatory networks. Here we have used a combination of global gene expression and chromatin-immunoprecipitation approaches during the early stages of haematopoietic development to define the transcriptional programme controlled by Runx1, an essential regulator of blood cell specification. Integrated analysis of these complementary genome-wide datasets allowed us to construct a global regulatory network model, which suggested that key regulators are activated sequentially during blood specification, but will ultimately collaborate to control many haematopoietically expressed genes. Using the CD41/integrin alpha 2b gene as a model, cellular and in vivo studies showed that CD41 is controlled by both Scl/Tal1 and Runx1 in fully specified blood cells, and initiation of CD41 expression in E7.5 embryos is severely compromised in the absence of Runx1. Taken together, this study represents the first global analysis of the transcriptional programme controlled by any key haematopoietic regulator during the process of early blood cell specification. Moreover, the concept of interplay between sequentially deployed core regulators is likely to represent a design principle widely applicable to the transcriptional control of mammalian development.

SUBMITTER: Tanaka Y

PROVIDER: S-EPMC3430866 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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The transcriptional programme controlled by Runx1 during early embryonic blood development.

Tanaka Yosuke Y Joshi Anagha A Wilson Nicola K NK Kinston Sarah S Nishikawa Shinichi S Göttgens Berthold B

Developmental biology 20120421 2

Transcription factors have long been recognised as powerful regulators of mammalian development yet it is largely unknown how individual key regulators operate within wider regulatory networks. Here we have used a combination of global gene expression and chromatin-immunoprecipitation approaches during the early stages of haematopoietic development to define the transcriptional programme controlled by Runx1, an essential regulator of blood cell specification. Integrated analysis of these complem ...[more]

PMID: 22554697

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Project description:The basic-helix-loop-helix transcription factor Scl/Tal1 controls the development and subsequent differentiation of haematopoietic stem cells (HSCs). However, since few Scl target genes have been validated to date, the underlying mechanisms have remained largely unknown. Here we have employed ChIP-Seq technology to generate a genome-wide catalogue of Scl binding events in a stem/progenitor cell line followed by validation using primary fetal liver cells and comprehensive transgenic mouse assays. Transgenic analysis provided in vivo validation of multiple new direct Scl target genes and allowed us to reconstruct an in vivo validated network consisting of 17 factors and their respective regulatory elements. By coupling ChIP-Seq in model cell lines with in vivo transgenic validation and sophisticated bioinformatic analysis, we have identified a widely applicable strategy for the reconstruction of stem cell regulatory networks where biological material is otherwise limiting. Moreover, in addition to revealing multiple previously unrecognised links to known HSC regulators as well as novel links to genes not previously implicated in HSC function, comprehensive transgenic analysis of regulatory elements provided substantial new insights into the transcriptional control of several important haematopoietic regulators including Cbfa2t3h/Eto2, Cebpe, Nfe2, Zfpm1/Fog1, Erg, Mafk, Gfi1b and Myb. Keywords: Gene regulation study Examination of one transcription factor in a haematopoietic progenitor cell line The samples provided were all sourced from the same ChIP experiment. They were then split into three and sent for sequencing. The samples labelled Scl_lane7 and Scl_lane8 were sequenced in parallel using an Illumina Genome Analyzer and then aligned using Solexa alignment software. There only variation was that the Scl_lane8 sample contained twice as much of the DNA as Scl_lane7. The sample labelled Scl_vancouver was sent to an alternative site for sequencing, again on an Illumina Genome Analyzer, and was aligned using the Eland aligner software.

Dataset Information

The transcriptional programme controlled by Runx1 during early embryonic blood development.

Publications

The transcriptional programme controlled by Runx1 during early embryonic blood development.

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