PT  - JOURNAL ARTICLE
AU  - Dahai Wang
AU  - Mayuri Tanaka-Yano
AU  - Eleanor Meader
AU  - Melissa A. Kinney
AU  - Vivian Morris
AU  - Edroaldo Lummertz da Rocha
AU  - Nan Liu
AU  - Stuart H. Orkin
AU  - Trista E. North
AU  - George Q. Daley
AU  - R. Grant Rowe
TI  - Developmental maturation of the hematopoietic system controlled by a Lin28b-<em>let</em>-<em>7</em>-PRC1 axis
AID  - 10.1101/2022.01.05.474696
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.05.474696
4099  - http://biorxiv.org/content/early/2022/01/05/2022.01.05.474696.short
4100  - http://biorxiv.org/content/early/2022/01/05/2022.01.05.474696.full
AB  - 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 and a precocious adult-like myeloid bias and that Cbx2/PRC1 regulates developmental timing of expression of key hematopoietic transcription factors. These findings define a novel mechanism of epigenetic regulation of HSPC output as a function of age with potential impact on age-biased pediatric and adult blood disorders.Competing Interest StatementG.Q.D. is a founder and shareholder of 28/7 Therapeutics.