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

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. [Display omitted] •Prepro-B is the crucial cellular stage at which PTEN controls hematopoietic lineage choices•PTEN loss alters chromatin accessibility and lineage potentials in prepro-B cells•PU.1 is a downstream effector of PTEN in regulating epigenetic states of prepro-B cells•Altering PU.1 level can reprogram lineage potentials of Ptennull prepro-B cells Xu et al. investigate PTEN’s role in hematopoietic lineage choices using integrated ATAC-seq, RNA-seq, and in vitro co-culture analyses. PTEN loss alters chromatin accessibility at the prepro-B stage, increasing myeloid/T-lineage potentials and reducing B-lineage potential. The underlying mechanism of PTEN-controlled PU.1 level in epigenetic modulation and lineage plasticity is highlighted.