Viewing AML through a New Lens: Technological Advances in the Study of Epigenetic Regulation

SIMPLE SUMMARY: Epigenetic mechanisms regulate gene expression in each cell type without modifying the underlying genetic sequence. These mechanisms are crucial for normal blood cell function. When they are disrupted, they give rise to diseases such as acute myeloid leukemia, an aggressive type of blood cancer. In this review, we outline the most recent technological advances that enable the study of the epigenetic mechanisms of blood cells with greater precision and a higher resolution. From the technologies that can introduce specific types of epigenetic changes ((epi)-genomic editing) to those that allow us to study the epigenetic mechanisms of individual cells, we summarize the advances which provide a new lens through which to study epigenetic regulation. Given the essential role of epigenetic mechanisms in healthy tissue function and disease, this can provide a comprehensive resource for researchers in the gene regulation field and beyond. ABSTRACT: Epigenetic modifications, such as histone modifications and DNA methylation, are essential for ensuring the dynamic control of gene regulation in every cell type. These modifications are associated with gene activation or repression, depending on the genomic context and specific type of modification. In both cases, they are deposited and removed by epigenetic modifier proteins. In acute myeloid leukemia (AML), the function of these proteins is perturbed through genetic mutations (i.e., in the DNA methylation machinery) or translocations (i.e., MLL-rearrangements) arising during leukemogenesis. This can lead to an imbalance in the epigenomic landscape, which drives aberrant gene expression patterns. New technological advances, such as CRISPR editing, are now being used to precisely model genetic mutations and chromosomal translocations. In addition, high-precision epigenomic editing using dCas9 or CRISPR base editing are being used to investigate the function of epigenetic mechanisms in gene regulation. To interrogate these mechanisms at higher resolution, advances in single-cell techniques have begun to highlight the heterogeneity of epigenomic landscapes and how these impact on gene expression within different AML populations in individual cells. Combined, these technologies provide a new lens through which to study the role of epigenetic modifications in normal hematopoiesis and how the underlying mechanisms can be hijacked in the context of malignancies such as AML.