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The miR-144/Hmgn2 regulatory axis orchestrates chromatin organization during erythropoiesis
Differentiation of stem and progenitor cells is a highly regulated process. Here, the authors uncover miR-144 and its target Hmgn2 as the backbone of the genetic regulatory circuit that controls the terminal differentiation of erythrocytes in vertebrates.
- Dmitry A. Kretov
- , Leighton Folkes
- & Daniel Cifuentes
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| Open Access
Increased iron uptake by splenic hematopoietic stem cells promotes TET2-dependent erythroid regeneration
The cues guiding hematopoietic stem cells (HSCs) to regenerate specific cell types lost due to injury remain elusive. This study shows that iron instructs erythroid differentiation of HSCs during anemia in a Tet2-dependent manner.
- Yu-Jung Tseng
- , Yuki Kageyama
- & Daisuke Nakada
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| Open Access
A transcriptional network governing ceramide homeostasis establishes a cytokine-dependent developmental process
Bioactive small molecules mediate transcription factor functions to control cellular processes. Here, Liao et al. discover that a GATA1-regulated metabolic enzyme controls ceramide homeostasis to commission vital cytokine signaling for erythropoiesis.
- Ruiqi Liao
- , Abiola Babatunde
- & Emery H. Bresnick
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Article
| Open Access
A unified model of human hemoglobin switching through single-cell genome editing
Genetic mechanisms underlying fetal hemoglobin (HbF) regulation and switching are not fully understood. Here, the authors develop a single-cell genome editing functional assay to model how effects of mutation-harbouring functional elements contribute to HbF expression.
- Yong Shen
- , Jeffrey M. Verboon
- & Vijay G. Sankaran
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Article
| Open Access
Reactivation of a developmentally silenced embryonic globin gene
Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.
- Andrew J. King
- , Duantida Songdej
- & Christian Babbs
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| Open Access
Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing
Ageing of the haematopoietic system is accompanied by declining erythropoiesis and lymphopoiesis. Here the authors uncover upregulated IL-6 and TGFβ signalling in aged bone marrow stroma; inhibition of these signals reverses age-related haematopoietic defects, re-balancing haematopoietic stem cell lineage output.
- Simona Valletta
- , Alexander Thomas
- & Claus Nerlov
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Article
| Open Access
Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype
The molecular basis of the clinically important MAM blood group antigen present in most humans is unknown. We identify EMP3 as its encoding gene, establishing MAM as a new blood group system, and demonstrate the role of EMP3 in erythropoiesis through its interaction with the signalling molecule CD44.
- Nicole Thornton
- , Vanja Karamatic Crew
- & David J. Anstee
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| Open Access
A revised model for promoter competition based on multi-way chromatin interactions at the α-globin locus
The coordination of interactions between multiple regulatory elements and genes within a chromatin domain remains poorly understood. Here, the authors use a method to detect multi-way chromatin interactions in a mouse model in which the α-globin domain is extended to include several additional genes, finding that the promoters do not form mutually exclusive interactions with the enhancers, but all interact simultaneously in a single complex.
- A. Marieke Oudelaar
- , Caroline L. Harrold
- & Jim R. Hughes
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Article
| Open Access
Genetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements
Here, the authors show that reticulocytes derived from immortalized erythroblasts support invasion and development of Plasmodium falciparum and use CRISPR-mediated gene knockout and complementation of an invasion receptor to demonstrate utility of this model system for research in malaria invasion.
- Timothy J. Satchwell
- , Katherine E. Wright
- & Jake Baum
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| Open Access
Genetic programming of macrophages generates an in vitro model for the human erythroid island niche
In vitro differentiation of red blood cells (RBCs) is a desirable therapy for various disorders. Here the authors develop a culture system using stem cell-derived macrophages to show that inducible expression of a transcription factor, KLF1, enhances RBC production, potentially through the induction of three soluble factors, ANGPTL7, IL33 and SERPINB2.
- Martha Lopez-Yrigoyen
- , Cheng-Tao Yang
- & Lesley M. Forrester
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Article
| Open Access
Long non-coding RNA-dependent mechanism to regulate heme biosynthesis and erythrocyte development
LncRNAs modulate diverse physiological cellular processes, however, their involvement in heme-dependent processes are not yet clear. Here the authors reveal the role of lncRNA UCA1 in erythroid cell development.
- Jinhua Liu
- , Yapu Li
- & Lihong Shi
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Article
| Open Access
P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim
Erythropoietin (EPO) stimulates erythropoiesis and is commonly used to treat anemia. Here Hu et al. find that P38α/JNK signaling restrains erythropoiesis independently of EPO by regulating epigenetic silencing of the proapoptotic protein Bim, and thus identify putative targets for the treatment of anemic disorders resistant to EPO.
- Ping Hu
- , Angel R. Nebreda
- & Reuben Kapur
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| Open Access
Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells
With age, haematopoietic stem cells (HSCs) produce more myeloid than lymphoid cells, affecting adaptive immunity. By combining HSC single cell transcriptomics with functional studies, Grover et al. find that platelet production is also increased in old murine HSCs and show that the FOG-1 transcription factor contributes to the age-dependent platelet bias.
- Amit Grover
- , Alejandra Sanjuan-Pla
- & Claus Nerlov
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| Open Access
STAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling
MicroRNAs regulate haematopoietic stem cell (HSC) development to ensure the correct generation of blood cells. Haetscher et al. show in mice that miR-193b controls the life-long self-renewal ability of HSCs via AKT and STAT5 pathways, with loss of miR-193b accelerating HSC expansion and reducing differentiation.
- Nadine Haetscher
- , Yonatan Feuermann
- & Michael A. Rieger
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| Open Access
Control of developmentally primed erythroid genes by combinatorial co-repressor actions
Conserved sets of transcription factors (TFs) regulate hematopoiesis. Here, Stadhouders et al. show that IRF2BP2 is a component of the LDB1 TF complex and together with its co-repressor ETO2, enhances transcriptional repression, which plays a crucial role at the erythroid progenitor stage.
- Ralph Stadhouders
- , Alba Cico
- & Eric Soler
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Article
| Open Access
Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality
What causes hematopoietic stem cell loss of functionality? Here, Alvarez et al. show that loss of origin licensing factor MCM3 induces replicative stress (RS), causing aberrant erythrocyte maturation, but mice strains with higher tolerance to RS can overcome this defect.
- Silvia Alvarez
- , Marcos Díaz
- & Juan Méndez
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Primitive macrophages control HSPC mobilization and definitive haematopoiesis
Haematopoietic stem/progenitor cells (HSPCs) transform from aortic endothelium into migratory cells that move through stroma and enter circulation to colonize haematopoietic tissues. Here the authors show that HSPCs' passage is facilitated by primitive macrophages that secrete extracellular matrix-degrading enzymes.
- Jana Travnickova
- , Vanessa Tran Chau
- & Karima Kissa
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| Open Access
miRNomes of haematopoietic stem cells and dendritic cells identify miR-30b as a regulator of Notch1
Several microRNAs have been implicated in the differentiation of immune cells. Here the authors analyse the global microRNA expression profiles of mouse haematopoietic stem cells and different stages of dendritic cell development and identify Notch1 as a target of miR-30b in regulatory dendritic cells.
- Xiaoping Su
- , Cheng Qian
- & Xuetao Cao
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Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis
The kidney and liver are the sources of erythropoietin required for definitive erythropoiesis, the second wave of erythrocyte formation for later embryonic and adult usage. Here the authors show that mouse embryonic neuroepithelial cells produce erythropoietin during mid-gestation, when primitive erythropoiesis occurs in the yolk sac.
- Norio Suzuki
- , Ikuo Hirano
- & Masayuki Yamamoto
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| Open Access
The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice
Post-translational modifications are important in regulating protein function and turnover, and Ufm1 is part of a recently identified protein modification system. In this study, the authors show that Uba5, a component of the Ufm1 system, is important for regulating haematopoiesis and the differentiation of erythroid cells.
- Kanako Tatsumi
- , Harumi Yamamoto-Mukai
- & Masaaki Komatsu
TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia