Tissue- and stage-specific roles of the ubiquitously expressed transcription factor sp1 in haematopoietic development

O'Connor, Leigh (2018). Tissue- and stage-specific roles of the ubiquitously expressed transcription factor sp1 in haematopoietic development. University of Birmingham. Ph.D.

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Abstract

Sp 1 is a ubiquitously expressed transcription factor and regulates a range of genes including housekeeping and tissue-specific genes. Studies using a DNA binding domain (DBD)-deficient Spl have shown that Spl is required for haematopoietic specification.

Here, we generated a Spl-DBD deficient ESC line to recapitulate the previous model, as well as a novel Spl null ESC line. Spl knockout cells demonstrated a complete absence ofhaematopoietic differentiation, indicating a crucial role for Sp 1 at the early stages of blood cell specification. In contrast, Sp 1 DBD-deficient cells were able to differentiate to haematopoietic progenitors, but failed to terminally differentiate, suggesting a different mechanism of Sp !-mediated transcriptional regulation in early and later stages. Gene expression analysis in Spl knockout cells indicated a novel role for Spl in ESC differentiation potential and mesoderm formation, while chromatin accessibility profiling revealed changes in chromatin structure in the absence ofSpl. We found Sp3, a close family member ofSpl , is able to compensate for loss ofSpl at most sites, but not at some important genes encoding developmental regulators. This work provides novel insights into the interplay between Sp 1 and Sp3 and furthers our understanding of the function of one of the earliest discovered TFs.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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