Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML. Significance: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a “writer–reader” epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587

Due to the complexity and limited availability of human brain tissues, for decades, pathologists have sought to maximize information gained from individual samples, based on which (patho)­physiological processes could be inferred. Recently, new understandings of chemical and physical properties of biological tissues and multiple chemical profiling have given rise to the development of scalable tissue clearing methods allowing superior optical clearing of across-the-scale samples. In the past decade, tissue clearing techniques, molecular labeling methods, advanced laser scanning microscopes, and data visualization and analysis have become commonplace. Combined, they have made 3D visualization of brain tissues with unprecedented resolution and depth widely accessible. To facilitate further advancements and applications, here we provide a critical appraisal of these techniques. We propose a classification system of current tissue clearing and expansion methods that allows users to judge the applicability of individual ones to their questions, followed by a review of the current progress in molecular labeling, optical imaging, and data processing to demonstrate the whole 3D imaging pipeline based on tissue clearing and downstream techniques for visualizing the brain. We also raise the path forward of tissue-clearing-based imaging technology, that is, integrating with state-of-the-art techniques, such as multiplexing protein imaging, in situ signal amplification, RNA detection and sequencing, super-resolution imaging techniques, multiomics studies, and deep learning, for drawing the complete atlas of the human brain and building a 3D pathology platform for central nervous system disorders.

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