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体内筛选鉴定正常和恶性造血过程中染色质因子的功能。

In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis.

机构信息

Department of Haematology, University of Cambridge, Cambridge, UK.

Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.

出版信息

Nat Genet. 2023 Sep;55(9):1542-1554. doi: 10.1038/s41588-023-01471-2. Epub 2023 Aug 14.

DOI:10.1038/s41588-023-01471-2
PMID:37580596
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10484791/
Abstract

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.

摘要

细胞分化需要染色质结构和功能的广泛改变，这是由染色质和转录因子的协调作用引起的。与转录因子不同，染色质因子在分化中的作用尚未得到系统表征。在这里，我们结合批量体外和单细胞体内 CRISPR 筛选，以表征染色质因子家族在造血中的作用。我们发现 142 种染色质因子具有明显的谱系特异性，揭示了相关染色质因子（即屏障到自动整合因子亚复合物）之间的功能多样性，以及无关抑制复合物在限制过度髓系分化方面的共同作用。通过表观遗传谱分析，我们确定了决定谱系的转录因子与几种染色质因子之间的功能相互作用，这些相互作用解释了它们的谱系依赖性。研究白血病中的染色质因子功能，我们表明白血病细胞利用体内稳态染色质因子功能来阻止分化，产生特定的染色质因子-转录因子相互作用，这些相互作用可能是治疗的靶点。总之，我们的工作阐明了染色质因子在正常和恶性造血中的谱系决定特性。

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