The MOE Key Laboratory of Cell Proliferation and Differentiation, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China; Center for Statistical Science, Peking University, Beijing, China.
The MOE Key Laboratory of Cell Proliferation and Differentiation, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Cell Rep. 2023 Aug 29;42(8):112967. doi: 10.1016/j.celrep.2023.112967. Epub 2023 Aug 9.
PTEN loss in fetal liver hematopoietic stem cells (HSCs) leads to alterations in myeloid, T-, and B-lineage potentials and T-lineage acute lymphoblastic leukemia (T-ALL) development. To explore the mechanism underlying PTEN-regulated hematopoietic lineage choices, we carry out integrated assay for transposase-accessible chromatin using sequencing (ATAC-seq), single-cell RNA-seq, and in vitro culture analyses using in vivo-isolated mouse pre-leukemic HSCs and progenitors. We find that PTEN loss alters chromatin accessibility of key lineage transcription factor (TF) binding sites at the prepro-B stage, corresponding to increased myeloid and T-lineage potentials and reduced B-lineage potential. Importantly, we find that PU.1 is an essential TF downstream of PTEN and that altering PU.1 levels can reprogram the chromatin accessibility landscape and myeloid, T-, and B-lineage potentials in Pten prepro-B cells. Our study discovers prepro-B as the key developmental stage underlying PTEN-regulated hematopoietic lineage choices and suggests a critical role of PU.1 in modulating the epigenetic state and lineage plasticity of prepro-B progenitors.
PTEN 缺失导致胎肝造血干细胞（HSCs）中髓系、T 系和 B 系潜能发生改变，并引发 T 系急性淋巴细胞白血病（T-ALL）。为了探究 PTEN 调控造血谱系选择的机制，我们采用转座酶可及染色质测序（ATAC-seq）、单细胞 RNA-seq 以及使用体内分离的小鼠前白血病 HSCs 和祖细胞进行体外培养分析，对其进行了综合检测。我们发现，PTEN 缺失会改变前 B 细胞阶段关键谱系转录因子（TF）结合位点的染色质可及性，从而增加髓系和 T 系潜能，降低 B 系潜能。重要的是，我们发现 PU.1 是 PTEN 的下游必需 TF，改变 PU.1 水平可以重新编程 Pten 前 B 细胞的染色质可及性图谱以及髓系、T 系和 B 系潜能。本研究发现前 B 细胞是 PTEN 调控造血谱系选择的关键发育阶段，并提示 PU.1 在调节前 B 祖细胞的表观遗传状态和谱系可塑性方面发挥着关键作用。
