Every human cell packs two metres of DNA into a nucleus the width of a hair, and a chemical tag called H3K23ac may be one of the key players that keeps that DNA properly folded and functional. This project tackles a fundamental gap in understanding how cells organise their genomes. Researchers know that mutations in the enzymes that add H3K23ac—KAT6A and KAT6B—cause severe developmental disorders and drive acute myeloid leukaemia, but no one knows exactly what H3K23ac does. The prevailing view holds that histone acetylation simply loosens DNA locally to let proteins in, but H3K23ac is so abundant across the genome that it likely plays a broader, structural role instead. The researcher will create new cell and mouse models to track H3K23ac in healthy and leukaemic cells, using genetic and genomic tools to map how its loss or misplacement alters genome organisation and triggers cancer. She will also develop two new methods—chromatin environment profiling and histone gene mutagenesis—that could transform how scientists study histone modifications in mammals. This is fundamental science. It will not produce a drug or diagnostic tomorrow. But understanding how chromatin architecture goes wrong in leukaemia could eventually reveal new targets for therapies, and the methods developed here may accelerate discovery across the entire field of epigenetics.
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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.
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