PhD defence R. (Roger) Mulet Lázaro

Summary:

Every day, the hematopoietic system produces billions of blood cells through the progressive specialization of hematopoietic stem cells (HSCs), a process known as hematopoiesis. Epigenetic mechanisms lie at the heart of this process, precisely establishing the transcriptional program of blood cells along the differentiation continuum. Disruptions in these mechanisms can give rise to dysregulation of genes critically involved in proliferation
or differentiation, ultimately resulting in leukemia. In fact, almost 75% of AML patients carry mutations in epigenetic modifiers. The concept of epigenetics as a bridge between genotype and phenotype was originally defined in the 1940s by Conrad Waddington, who metaphorically depicted the epigenetic landscape as hilly slope that guides cell
differentiation. Our understanding of epigenetics has come a long way since those early days, and the valleys and ridges in Waddington’s model are no longer seen as theoretical constructs, but measurable features such as DNA methylation, histone acetylation and transcription factor binding. The addition of next generation sequencing (NGS) technologies to the arsenal of the molecular biologist has made it possible to chart the epigenetic landscape of entire genomes, even in single cells. Nevertheless, this unprecedented wealth of data has come with its own unique set of challenges, namely in terms of data analysis and interpretation – bioinformatics has emerged as an indispensable discipline to face these challenges.

The work presented in this thesis draws from molecular biology and bioinformatics alike to shed light on the role of transcription factors (TF) in healthy hematopoiesis, explore the mechanisms of enhancer hijacking in leukemia and identify novel epigenetic events underlying leukemogenesis.