Abstract：
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 Ptennull 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.
摘要：
胎儿肝脏造血干细胞（HSC）中的PTEN丢失导致骨髓改变，T-,和B谱系潜能和T谱系急性淋巴细胞白血病（T-ALL）的发展。为了探索PTEN调节的造血谱系选择的潜在机制，我们使用测序（ATAC-seq）对转座酶可接近的染色质进行整合测定，单细胞RNA-seq，使用体内分离的小鼠白血病前HSC和祖细胞进行体外培养分析。我们发现PTEN缺失会改变前B阶段关键谱系转录因子（TF）结合位点的染色质可及性，对应于增加的骨髓和T谱系电位和降低的B谱系电位。重要的是,我们发现PU.1是PTEN下游的重要TF，改变PU.1水平可以重新编程染色质可及性景观和骨髓，T-,和Ptennullprepro-B细胞中的B谱系电位。我们的研究发现prepro-B是PTEN调节的造血谱系选择的关键发育阶段，并表明PU.1在调节prepro-B祖细胞的表观遗传状态和谱系可塑性中的关键作用。
