PTEN regulates hematopoietic lineage plasticity via PU.1-dependent chromatin accessibility

作者：Zihan Xu, Libing He, Yilin Wu, Lu Yang, Cheng Li, Hong Wu · 发表于：Cell Reports · 年份：2023 · DOI：10.1016/j.celrep.2023.112967 · 被引用次数：10 · 研究领域：Acute Lymphoblastic Leukemia research、Acute Myeloid Leukemia Research、RNA modifications and cancer

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 null 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.