Medical Biology - Theses

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The role of HBO1 during embryonic development

Kueh, Andrew Jing Yaw ( 2012)

This thesis presents the first in vivo characterisation of HBO1 (histone acetyltransferase bound to ORC1; MYST2/KAT7) function at the molecular and cellular level. Specifically, HBO1 function was investigated during (a) early embryonic development, by analysing Hbo1 null mutant mice and (b) in brain development during late gestation, by analysing conditional transgenic mice displaying HBO1 deficiency in the central nervous system. HBO1 is essential for H3K14 acetylation (H3K14ac) and the activation of key developmental regulatory genes in both mouse models. In the first study, this process is crucial for the patterning of rapidly differentiating embryonic tissues such as the mesenchyme, vasculature, heart and neural tube during post-gastrulation development. In the second study, HBO1 mediated H3K14ac is indispensible for the expression of genes required for neuronal lineage commitment and differentiation. During embryonic brain development, HBO1 is critical for dentate gyrus patterning, neuronal migration, cortical lamination and layer specific gene expression. Unexpectedly, in contrast to numerous earlier reports implicating HBO1 in DNA replication, this thesis demonstrates that HBO1 is not essential for DNA replication. Together, in vivo and in vitro data presented in this thesis illustrate the dependency on HBO1 for H3K14ac, transcriptional activation and cellular differentiation.