Inhibition of aryl hydrocarbon receptor signaling promotes the terminal differentiation of human erythroblasts

Chen, Yijin; Dong, Yong; Lu, Xulin; Li, Wanjing; Zhang, Yimeng; Mao, Bin; Xu, Pan; Li, Xiaohong; Zhou, Yifeng; An, Quanming; Xie, Fangxin; Wang, Shihui; Xue, Yan; Cai, Xinping; Lai, Mowen; Zhou, Qi; Yan, Yan; Fu, Ruohan; Wang, Hong; Nakahata, Tatsutoshi; An, Xiuli; Shi, Lihong; Yong-gang, Zhang; Ma, Feng

doi:10.1093/jmcb/mjac001

Cited by 11 publications

(8 citation statements)

References 52 publications

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“…The percentage of AHR sense expressing cells also decreased dramatically, from approximately 40% in progenitors, to ~10% in immature NK cells, and less than 2% in mature NK cells. This indicates that AHR is downregulated during differentiation, in line with observations that AHR antagonism increases NK cell differentiation (Lordo et al, 2021; Chen et al, 2022).…”

Section: Resultssupporting

confidence: 88%

“…The presence of an opposing promoter in the first intron of the AHR gene (asPro1), potentially creating an on/off-switch, is intriguing, especially with regard to a recent study that demonstrated the ability of AHR antagonists to enhance ESC differentiation (Chen et al, 2022). If the function of the asPro1 promoter is to downregulate AHR expression in differentiating cells, then its expression should be limited to early progenitors.…”

Section: Resultsmentioning

confidence: 99%

“…Weak expression of the asPro2 transcript was detected in a small number of cells in tonsil tissue, indicating that antisense transcription may be a rare event associated with differentiating cells, or the antisense transcript is highly unstable (Figure 2E). The presence of an opposing promoter in the first intron of the AHR gene (asPro1), potentially creating an on/off-switch, is intriguing, especially with regard to a recent study that demonstrated the ability of AHR antagonists to enhance ESC differentiation (Chen et al, 2022).…”

Section: The Ahr Gene Contains a Bidirectional Promoter And Adjacent ...mentioning

confidence: 99%

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Evidence for the digital programming of cellular differentiation: characterization of binary switches in lineage-determining transcription factors

Rahman

Wright

et al. 2022

Preprint

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Previous studies of the murine Ly49 and human KIR gene clusters have revealed a role for bidirectional promoters in the control of variegated gene expression. Whether or not competing promoters control other instances of cell fate determination remains an outstanding question. Although divergent transcripts within 300 bp are found in ~6% of human genes, an analysis of human transcription factor (TF) genes (1640) revealed that 33% possess stable divergent transcripts with a transcription start site (TSS) less than 300 bp upstream, with many separated by less than 30 bp, indicating an enrichment for potential binary switches in TFs. We have performed a detailed examination of putative bidirectional promoter switches in three lineage-determining TF genes: AHR, GATA3, and RORC. These genes also contain additional pairs of opposing promoters that would prevent simultaneous transcription of sense and antisense, and thus may represent simple on/off switches rather than probabilistic switches. In situ RNA hybridization of human tissues revealed mutually exclusive expression of sense versus antisense transcription, indicating switching between stable sense or antisense transcriptional states. Single-cell RNAseq confirmed the separate sense/antisense states, and revealed the identity of cells with active switch elements. Differential gene expression analysis of cells with antisense switch transcripts revealed an enrichment for genes found in immature/stem cells and a lack of genes associated with terminally differentiated cells. Taken together, these data indicate that there is a digital component to the differentiation program mediated by binary promoter switches in lineage-determining transcription factors.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: The Ahr Gene Contains a Bidirectional Promoter And Adjacent ...mentioning

confidence: 99%

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Evidence for the digital programming of cellular differentiation: characterization of binary switches in lineage-determining transcription factors

Rahman

Wright

et al. 2022

Preprint

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“…In this sense, alternative protocols that show highly efficient production of hemoglobin β using different approaches, such as immortalization of erythroid precursor cells and modulation of BCL11A expression [ 25 , 26 , 63 ], in vivo maturation in NOD/SCID mice [ 64 ], or using cells treated with human platelet lysate [ 63 ], should be further assessed. Recently, Chen et al reported that erythroid terminal differentiation was improved in a culture of HSPCs derived from human embryonic stem cells by adding an aryl hydrocarbon receptor antagonist [ 65 ], and this represents a less laborious approach that is compatible with SCD disease models.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of 2D and 3D Erythroid Differentiation Protocols Using Sickle Cell Disease and Healthy Donor Induced Pluripotent Stem Cells

Martins

Nonaka

Rossi

et al. 2023

Cells

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Background: Sickle cell disease (SCD) is a highly prevalent genetic disease caused by a point mutation in the HBB gene, which can lead to chronic hemolytic anemia and vaso-occlusive events. Patient-derived induced pluripotent stem cells (iPSCs) hold promise for the development of novel predictive methods for screening drugs with anti-sickling activity. In this study, we evaluated and compared the efficiency of 2D and 3D erythroid differentiation protocols using a healthy control and SCD-iPSCs. Methods: iPSCs were subjected to hematopoietic progenitor cell (HSPC) induction, erythroid progenitor cell induction, and terminal erythroid maturation. Differentiation efficiency was confirmed by flow cytometry analysis, colony-forming unit (CFU) assay, morphological analyses, and qPCR-based gene expression analyses of HBB and HBG2. Results: Both 2D and 3D differentiation protocols led to the induction of CD34+/CD43+ HSPCs. The 3D protocol showed good efficiency (>50%) and high productivity (45-fold) for HSPC induction and increased the frequency of BFU-E, CFU-E, CFU-GM, and CFU-GEMM colonies. We also produced CD71+/CD235a+ cells (>65%) with a 630-fold cell expansion relative to that at the beginning of the 3D protocol. After erythroid maturation, we observed 95% CD235a+/DRAQ5- enucleated cells, orthochromatic erythroblasts, and increased expression of fetal HBG2 compared to adult HBB. Conclusion: A robust 3D protocol for erythroid differentiation was identified using SCD-iPSCs and comparative analyses; however, the maturation step remains challenging and requires further development.

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“…Peripheral blood counts were measured by SYSMEX XT-1800i. Blood smear was stained by May-Grunwald Giemsa (MGG) as described previously [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells

Dong

Cao

et al. 2022

Cells

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Myosin heavy chain 9 (MYH9) gene encodes a protein named non-muscle heavy chain IIA (NMHC IIA), interacting with actin and participating in various biological processes. Mutations in MYH9 cause an array of autosomal dominant disorders, known as MYH9-related diseases (MYH9-RD). However, the role of MYH9 in normal hematopoiesis remains largely unexplored. By using Mx1-cre Myh9 conditional knockout mice, we established an inducible system to precisely inactivate Myh9 function in hematopoietic cells in vivo. The results showed that deletion of Myh9 led to severe defects in hematopoiesis, characterized by pancytopenia, drastic decreases of hematopoietic stem/progenitor cells (HSPC), and bone marrow failure, causing early lethality in mice. The defect in hematopoiesis caused by Myh9 ablation is cell autonomous. In addition, Myh9 deletion impairs HSPC repopulation capacity and increases apoptosis. RNA sequencing results revealed significant alterations in the expression of genes related to HSC self-renewal and maintenance, while multiple signal pathways were also involved, including genes for HSC and myeloid cell development, intrinsic apoptosis, targets of mTOR signaling, and maturity of hematopoietic cells. Our present study suggests an essential role for Myh9 in the survival and maintenance of HSPC in normal hematopoiesis.

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Inhibition of aryl hydrocarbon receptor signaling promotes the terminal differentiation of human erythroblasts

Cited by 11 publications

References 52 publications

Evidence for the digital programming of cellular differentiation: characterization of binary switches in lineage-determining transcription factors

Evidence for the digital programming of cellular differentiation: characterization of binary switches in lineage-determining transcription factors

Evaluation of 2D and 3D Erythroid Differentiation Protocols Using Sickle Cell Disease and Healthy Donor Induced Pluripotent Stem Cells

Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells

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