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Novel roles of KAT2A chromatin complexes ATAC and SAGA in normal and malignant haematopoiesis



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De Jesus Arede, Liliana 


Haematopoiesis is a dynamic process by which the full array of blood cell types originates from multipotent haematopoietic stem cells (HSCs). The blood system has long been an attractive model to explore how cell fate decisions are conducted at the molecular level, to generate the vast diversity of blood cell types. Blood cell fate choice is for the most part regulated by transcription factors and epigenetic modifiers. The enzymatic activities of epigenetic regulators are of particular importance in malignant haematopoiesis such as leukaemia, given their reversible nature and potential for therapeutic targeting. Epigenetic histone modifiers are often found within large multi-subunit complexes, whereby their catalytic activity is exercised. However, very little is known about how epigenetic enzymes take advantage of their participating chromatin complexes in order to accomplish their functions. In the blood system, no studies have formally examined how different epigenetic complexes with the same enzymatic component coordinate cell fate choices. Here, I focus on KAT2A, a lysine acetyltransferase responsible for Histone 3 Lysine 9 acetylation (H3K9ac), and a vulnerability in Acute Myeloid Leukaemia (AML), as well as its 2 containing complexes: Ada-Two-A-Containing (ATAC) and Spt-Ada-Gcn5-Acetyltransferase (SAGA). I combine cell functional and molecular assays of human cord blood (CB) haematopoietic cells and AML cells to dissect KAT2A roles depending on its participation in ATAC or SAGA complexes. Firstly, I demonstrate that KAT2A regulates CB erythroid progenitor specification and survival. I uncover unique contributions of the ATAC complex to erythroid lineage specification, whereas SAGA acts late in differentiation. This suggests that KAT2A plays stage-specific roles, which are unique to the complexes it integrates. While KAT2A regulates specification and survival of erythroid progenitors via ATAC through control of biosynthetic activity, it fine-tunes progression of erythroid differentiation through participation in SAGA. Secondly, I explored the roles of ATAC and SAGA in leukaemic haematopoiesis. I found that ATAC regulates proliferation through control of biosynthetic activity. Instead, SAGA participates in maintenance of the characteristic block in AML cell differentiation, compatible with a generic control of cell identity through preservation of cell-type specific transcriptional programmes. My data is consistent with a model in which the ATAC complex has pervasive roles in maintenance of self-renewing cells, while SAGA acts to stabilise cell-type specific programmes, preserving cell identity. Understanding ATAC and SAGA unique chromatin regulatory mechanisms has important implications for the tailored design of new drugs for clinical application.





Pina, Cristina


KAT2A, ATAC complex, SAGA complex, epigenetics, haematopoiesis, acute myeloid leukaemia


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Rosetrees Trust (M650)
Rosetrees Trust PhD Studentship Academic Merit Scholarship - Santander Universities UK The Sir Richard Stapley Educational Trust