细胞分化需要广泛改变染色质结构和功能，这是由染色质和转录因子的协调作用引发的。与转录因子相比，染色质因子在分化中的作用尚未系统地进行表征。在这里，我们结合体外大量和体内单细胞CRISPR筛选，表征了染色质因子家族在造血过程中的作用。我们发现了142个染色质因子的明显亚型特异性，揭示了相关染色质因子（如阻拦自体整合因子亚复合体）之间的功能多样性，以及无关的抑制性复合物在阻止过度髓系分化中的共同角色。利用表观遗传学分析，我们发现了线粒体决定转录因子与几个染色质因子之间的功能相互作用，解释了它们的亚型依赖性。通过研究白血病中的染色质因子功能，我们展示了白血病细胞利用稳态染色质因子功能阻断分化的机制，并产生了特定的染色质因子-转录因子相互作用，这可能成为治疗靶点。总之，我们的研究阐明了正常和恶性造血过程中染色质因子的线粒体决定性质。© 2023作者。

Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis.© 2023. The Author(s).