Induction of 'Hox' genes and genome wide identification of Hox binding sites in mice

De Kumar, Bony (2013). Induction of 'Hox' genes and genome wide identification of Hox binding sites in mice. PhD thesis The Open University.



Hox genes encode a family of transcription factors that play highly conserved regulatory roles in specifying the properties of tissues in developing embryos. Very little is known about how HOX proteins control the cellular and developmental processes governing morphogenesis through regulation of down-stream target genes. The goal of this research was to investigate on a genome-wide basis, the rules and principles which underlie the binding of different HOX proteins to target sites and understand the basis for their distinct specificities. I utilized the programmed differentiation of mouse embryonic stem cells into a neural fate with retinoids and genomic technologies to systematically investigate binding properties of two HOX proteins, HOXA1 and HOXBI and their cofactors PBX and MEIS. I analyzed the induction properties of the cells and the transcriptional dynamics and epigenetic states in Hox clusters to explore the differentiation process. An extensive and dynamic pattern of transcriptional activity indicates that Hox clusters generate a large number of non-coding RNAs which may impact their activation and chromatin states. Global identification of HOXB1, HOXA1, PBX and MEIS binding regions by chromatin immune precipitation and high throughout sequencing (ChIP-seq) has generated insight into many potential Hox target genes. HOXA1 binding peaks generally overlapped with those of PBX and MEIS, supporting their roles as HOX co-factors. The sites bound by HOXBl uncovered new classes of binding motifs. Regulatory assays demonstrated that many of these novel motifs functioned as neuronal enhancers. Many HOXB1 binding peaks have closely associated REST motifs and bind the REST repressor complex, which is important in neuronal differentiation. The close association of REST and HOXB1 binding sites provides a mechanism for coordinating cell differentiation programs in neurogenesis. This research has uncovered novel properties of HO X proteins and their co-factors that underlie their role as master regulators of patterning and morphogenesis.

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