Developmental maturation of the hematopoietic system controlled by a Lin28b-let-7-Cbx2 axis
Dahai Wang,
Mayuri Tanaka-Yano,
Eleanor Meader,
Melissa A. Kinney,
Vivian Morris,
Edroaldo Lummertz da Rocha,
Nan Liu,
Tianxin Liu,
Qian Zhu,
Stuart H. Orkin,
Trista E. North,
George Q. Daley,
R. Grant Rowe
Affiliations
Dahai Wang
Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA
Mayuri Tanaka-Yano
Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA
Eleanor Meader
Stem Cell Program, Boston Children’s Hospital, Boston, MA 02115, USA
Melissa A. Kinney
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
Vivian Morris
Stem Cell Program, Boston Children’s Hospital, Boston, MA 02115, USA
Edroaldo Lummertz da Rocha
Department of Microbiology, Immunology, and Parasitology, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil
Nan Liu
Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA
Tianxin Liu
Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA
Qian Zhu
Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA
Stuart H. Orkin
Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Boston Children’s Cancer and Blood Disorders Center, Boston, MA 02115, USA
Trista E. North
Stem Cell Program, Boston Children’s Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
George Q. Daley
Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA; Stem Cell Program, Boston Children’s Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
R. Grant Rowe
Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA; Stem Cell Program, Boston Children’s Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Boston Children’s Cancer and Blood Disorders Center, Boston, MA 02115, USA; Stem Cell Transplantation Program, Boston Children’s Hospital, Boston, MA 02115, USA; Corresponding author
Summary: Hematopoiesis changes over life to meet the demands of maturation and aging. Here, we find that the definitive hematopoietic stem and progenitor cell (HSPC) compartment is remodeled from gestation into adulthood, a process regulated by the heterochronic Lin28b/let-7 axis. Native fetal and neonatal HSPCs distribute with a pro-lymphoid/erythroid bias with a shift toward myeloid output in adulthood. By mining transcriptomic data comparing juvenile and adult HSPCs and reconstructing coordinately activated gene regulatory networks, we uncover the Polycomb repressor complex 1 (PRC1) component Cbx2 as an effector of Lin28b/let-7’s control of hematopoietic maturation. We find that juvenile Cbx2−/− hematopoietic tissues show impairment of B-lymphopoiesis, a precocious adult-like myeloid bias, and that Cbx2/PRC1 regulates developmental timing of expression of key hematopoietic transcription factors. These findings define a mechanism of regulation of HSPC output via chromatin modification as a function of age with potential impact on age-biased pediatric and adult blood disorders.
