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Regulation of lymphoid-myeloid lineage bias through Regnase-1/3-mediated control of Nfkbiz

Item Type:Article
Title:Regulation of lymphoid-myeloid lineage bias through Regnase-1/3-mediated control of Nfkbiz
Creators Name:Uehata, T. and Yamada, S. and Ori, D. and Vandenbon, A. and Giladi, A. and Jelinski, A. and Murakawa, Y. and Watanabe, H. and Takeuchi, K. and Toratani, K. and Mino, T. and Kiryu, H. and Standley, D.M. and Tsujimura, T. and Ikawa, T. and Kondoh, G. and Landthaler, M. and Kawamoto, H. and Rodewald, H.R. and Amit, I. and Yamamoto, R. and Miyazaki, M. and Takeuchi, O.
Abstract:Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that mRNA decay factors Regnase-1 (Reg1; Zc3h12a) and Regnase-3 (Reg3; Zc3h12c) are essential for determining lymphoid fate and restricting myeloid differentiation in HSPCs. Loss of Reg1 and Reg3 resulted in severe impairment of lymphopoiesis and a mild increase in myelopoiesis in the BM. single cell RNA sequencing analysis (scRNA-seq) revealed that Reg1 and Reg3 regulate lineage directions in HSPCs via the control of a set of myeloid-related genes. Reg1- and Reg3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single cell-assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis revealed that Reg1 and Reg3 control the epigenetic landscape on myeloid-related gene loci in early-stage HSPCs via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Reg1- and Reg3-mediated Nfkbiz mRNA degradation primed HSCs toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between post-transcriptional control and chromatin remodeling by the Reg1/Reg3-Nfkbiz axis governs HSPC lineage biases, ultimately dictating the fate of lymphoid versus myeloid differentiation.
Keywords:Bone Marrow, Cell Differentiation, Cell Lineage, Hematopoiesis, Hematopoietic Stem Cells, Messenger RNA
Publisher:American Society of Hematology
Page Range:243-257
Date:18 January 2024
Official Publication:https://doi.org/10.1182/blood.2023020903
PubMed:View item in PubMed

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