Investigating the functions of histone acetylation in genome organization and leukemogenesis
Lead Research Organisation:
Institute of Cancer Research
Department Name: Division of Cancer Biology
Abstract
Chromatin structure plays a central role in controlling cell phenotype. This is highlighted by altered epigenomes and frequent mutations in chromatin regulators in cancer cells. Despite recent advances in epigenetics, we currently lack detailed mechanistic understanding of how chromatin organization contributes to gene expression, genome stability and cancer initiation, which hinders development of efficient therapies.
Acetylation of histone proteins is considered to facilitate local DNA access for regulators of genomic processes such as transcription, replication, and repair. Acetylation of histone H3 on lysine 23 (H3K23ac) stands out among other acetylation sites due its high abundance in mammalian chromatin, which challenges the generally assumed local DNA accessibility role and instead suggests a function in more global processes of genome organization. Knockouts of the enzymes placing H3K23ac, KAT6A and KAT6B, have strong developmental phenotypes. Moreover, chromosomal translocations generating KAT6A- or KAT6B-containing fusion proteins induce acute myeloid leukemia. Together, these observations indicate an important yet unexplored role of H3K23ac in regulating cell phenotype.
I hypothesize that H3K23ac confers a specific chromatin structure that ensures correct genomic organisation and which misregulation induces leukemia. To investigate this, I will develop novel cell and mouse models and will use a combination of cutting-edge genetic, genomic and cell biology approaches to investigate the role of H3K23ac in normal and leukemic cells. In addition, I will establish several key methodologies (chromatin environment profiling and histone gene mutagenesis) that will transform the way histone modifications are investigated in mammals. In the long-term, the proposed work will serve as a strong conceptual and methodological foundation to answer the fundamental questions of how chromatin structure and function influence cell phenotype and induce disease.
Acetylation of histone proteins is considered to facilitate local DNA access for regulators of genomic processes such as transcription, replication, and repair. Acetylation of histone H3 on lysine 23 (H3K23ac) stands out among other acetylation sites due its high abundance in mammalian chromatin, which challenges the generally assumed local DNA accessibility role and instead suggests a function in more global processes of genome organization. Knockouts of the enzymes placing H3K23ac, KAT6A and KAT6B, have strong developmental phenotypes. Moreover, chromosomal translocations generating KAT6A- or KAT6B-containing fusion proteins induce acute myeloid leukemia. Together, these observations indicate an important yet unexplored role of H3K23ac in regulating cell phenotype.
I hypothesize that H3K23ac confers a specific chromatin structure that ensures correct genomic organisation and which misregulation induces leukemia. To investigate this, I will develop novel cell and mouse models and will use a combination of cutting-edge genetic, genomic and cell biology approaches to investigate the role of H3K23ac in normal and leukemic cells. In addition, I will establish several key methodologies (chromatin environment profiling and histone gene mutagenesis) that will transform the way histone modifications are investigated in mammals. In the long-term, the proposed work will serve as a strong conceptual and methodological foundation to answer the fundamental questions of how chromatin structure and function influence cell phenotype and induce disease.
