Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells

Experimental Hematology
Motohiko OshimaAtsushi Iwama

Abstract

Fetal liver hematopoietic stem cells (HSCs) seed bone marrow (BM) and undergo reprograming into adult-type HSCs that are largely quiescent and restricted in their self-renewal activity. Here we report that in the absence of the polycomb-group gene Ezh2, a cohort of fetal-specific genes, including let-7 target genes, were activated in BM hematopoietic stem/progenitor cells (HSPCs), leading to acquisition of fetal phenotypes by BM HSPCs, such as enhanced self-renewal activity and production of fetal-type lymphocytes. The Lin28b/let-7 pathway determines developmentally timed changes in HSPC programs. Of note, many of the fetal-specific let-7 target genes, including Lin28, appear to be transcriptionally repressed by Ezh2-mediated H3K27me3 in BM HSPCs, and Ezh2 loss results in their ectopic expression, particularly in hematologic malignancies that develop in the absence of Ezh2. These findings suggest that Ezh2 cooperates with let-7 microRNAs in silencing the fetal gene signature in BM HSPCs and restricts their transformation.

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Citations

May 31, 2016·Clinical Epigenetics·Koraljka Gall TrošeljDjurdjica Ugarkovic
Aug 4, 2018·Genome Research·Lucas A SalasKarl T Kelsey
Jul 25, 2017·The Journal of Physiology·Alessandra CastaldiNicole H Purcell
Jan 4, 2018·Blood Advances·Koki UedaYasuchika Takeishi
Dec 6, 2019·British Journal of Haematology·Luke JonesJonathan Bond
Feb 26, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jennifer A JacobsenBarbara L Kee
Aug 29, 2019·Regenerative Medicine·Michael D WestDana Larocca
Jul 8, 2020·The Journal of Clinical Investigation·Jessica LovnickiXuesen Dong
Feb 6, 2020·Proceedings of the National Academy of Sciences of the United States of America·Xijin XuRichard J Cornall
Nov 5, 2020·Immunological Reviews·Maria PapadopoulouDavid Vermijlen
Jan 7, 2021·Cell Reports·Koichi MurakamiHideaki Nakajima
Sep 24, 2019·Advances in Biological Regulation·Samuel GusscottAndrew P Weng
Dec 18, 2020·Frontiers in Immunology·Lijun YangQing Ge
Dec 12, 2020·International Journal of Molecular Sciences·Toshiyuki Yamane
Dec 31, 2020·International Journal of Molecular Sciences·Satoshi Kaito, Atsushi Iwama

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