Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells.
Stefan Rentas, Nicholas Holzapfel, Muluken S Belew, Gabriel Pratt, Veronique Voisin, Brian T Wilhelm, Gary D Bader, Gene W Yeo, Kristin J Hope
Nature · 2016 · Vol. 532 (7600) · pp. 508-511
Abstract
Umbilical cord blood-derived haematopoietic stem cells (HSCs) are essential for many life-saving regenerative therapies. However, despite their advantages for transplantation, their clinical use is restricted because HSCs in cord blood are found only in small numbers. Small molecules that enhance haematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified, but in many cases their mechanisms of action or the nature of the pathways they impinge on are poorly understood. A greater understanding of the molecular circuitry that underpins the self-renewal of human HSCs will facilitate the development of targeted strategies that expand HSCs for regenerative therapies. Whereas transcription factor networks have been shown to influence the self-renewal and lineage decisions of human HSCs, the post-transcriptional mechanisms that guide HSC fate have not been closely investigated. Here we show that overexpression of the RNA-binding protein Musashi-2 (MSI2) induces multiple pro-self-renewal phenotypes, including a 17-fold increase in short-term repopulating cells and a net 23-fold ex vivo expansion of long-term repopulating HSCs. By performing a global analysis of MSI2-RNA interactions, we show that MSI2 directly attenuates aryl hydrocarbon receptor (AHR) signalling through post-transcriptional downregulation of canonical AHR pathway components in cord blood HSPCs. Our study gives mechanistic insight into RNA networks controlled by RNA-binding proteins that underlie self-renewal and provides evidence that manipulating such networks ex vivo can enhance the regenerative potential of human HSCs.
Linked datasets 2
Musashi-2 Post-transcriptionally Attenuates Aryl Hydrocarbon Receptor Signaling to Expand Human Hematopoietic Stem Cells
Homo sapiens
4 data files
| File | Type | Size |
|---|---|---|
| MSI2_ACAGTG_ACAGTG_L008_R1.fastq.gz | OTHER | 1.1 GB |
| MSI2_TTAGGC_TTAGGC_L008_R1.fastq.gz | OTHER | 1.6 GB |
| SRR2051419_GSM1704212 | OTHER | 1.1 GB |
| SRR2051420_GSM1704213 | OTHER | 1.6 GB |
Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells
Homo sapiens
55 data files
| File | Type | Size |
|---|---|---|
| MA_248_C349KACXX_L005_R1.fastq.gz | RNA-Seq | 1.8 GB |
| MA_248_C349KACXX_L005_R2.fastq.gz | RNA-Seq | 1.8 GB |
| MA_248_C349KACXX_L006_R1.fastq.gz | RNA-Seq | 2.2 GB |
| MA_248_C349KACXX_L007_R1.fastq.gz | RNA-Seq | 1.8 GB |
| MA_254_C349KACXX_L005_R1.fastq.gz | RNA-Seq | 1.9 GB |
| MA_254_C349KACXX_L006_R1.fastq.gz | RNA-Seq | 2.4 GB |
| MA_254_C349KACXX_L007_R1.fastq.gz | RNA-Seq | 1.9 GB |
| MA_MSI2_248_C349KACXX_L005_R1.fastq.gz | RNA-Seq | 1.8 GB |
| MA_MSI2_248_C349KACXX_L006_R1.fastq.gz | RNA-Seq | 2.2 GB |
| MA_MSI2_248_C349KACXX_L006_R2.fastq.gz | RNA-Seq | 2.2 GB |
| MA_MSI2_248_C349KACXX_L007_R1.fastq.gz | RNA-Seq | 1.8 GB |
| MA_MSI2_254_C349KACXX_L005_R1.fastq.gz | RNA-Seq | 1.9 GB |
| MA_MSI2_254_C349KACXX_L006_R1.fastq.gz | RNA-Seq | 2.3 GB |
| MA_MSI2_254_C349KACXX_L007_R1.fastq.gz | RNA-Seq | 1.9 GB |
| MA_MSI2_254_C349KACXX_L007_R2.fastq.gz | RNA-Seq | 1.9 GB |
| sh332_248_C349KACXX_L005_R1.fastq.gz | RNA-Seq | 1.8 GB |
| sh332_248_C349KACXX_L006_R1.fastq.gz | RNA-Seq | 2.2 GB |
| sh332_248_C349KACXX_L007_R1.fastq.gz | RNA-Seq | 1.8 GB |
| sh332_254_C349KACXX_L005_R1.fastq.gz | RNA-Seq | 1.9 GB |
| sh332_254_C349KACXX_L006_R1.fastq.gz | RNA-Seq | 2.3 GB |
| sh332_254_C349KACXX_L007_R1.fastq.gz | RNA-Seq | 1.9 GB |
| sh332_254_C349KACXX_L007_R2.fastq.gz | RNA-Seq | 1.9 GB |
| shRFP_248_C349KACXX_L005_R1.fastq.gz | RNA-Seq | 1.9 GB |
| shRFP_248_C349KACXX_L006_R1.fastq.gz | RNA-Seq | 2.3 GB |
| shRFP_248_C349KACXX_L007_R1.fastq.gz | RNA-Seq | 1.9 GB |
| shRFP_254_C349KACXX_L005_R1.fastq.gz | RNA-Seq | 1.8 GB |
| shRFP_254_C349KACXX_L006_R1.fastq.gz | RNA-Seq | 2.1 GB |
| shRFP_254_C349KACXX_L007_R1.fastq.gz | RNA-Seq | 1.8 GB |
| SRR2095416_GSM1816429 | RNA-Seq | 1.8 GB |
| SRR2095417_GSM1816429 | RNA-Seq | 2.2 GB |
| SRR2095418_GSM1816429 | RNA-Seq | 1.8 GB |
| SRR2095419_GSM1816430 | RNA-Seq | 1.9 GB |
| SRR2095420 | RNA-Seq | 2.3 GB |
| SRR2095420_GSM1816430 | RNA-Seq | 2.3 GB |
| SRR2095421_GSM1816430 | RNA-Seq | 1.9 GB |
| SRR2095422_GSM1816431 | RNA-Seq | 1.8 GB |
| SRR2095423 | RNA-Seq | 2.2 GB |
| SRR2095423_GSM1816431 | RNA-Seq | 2.2 GB |
| SRR2095424_GSM1816431 | RNA-Seq | 1.8 GB |
| SRR2095425_GSM1816432 | RNA-Seq | 1.9 GB |
| SRR2095426_GSM1816432 | RNA-Seq | 2.4 GB |
| SRR2095427_GSM1816432 | RNA-Seq | 1.9 GB |
| SRR2095428_GSM1816433 | RNA-Seq | 1.8 GB |
| SRR2095429_GSM1816433 | RNA-Seq | 2.2 GB |
| SRR2095430_GSM1816433 | RNA-Seq | 1.8 GB |
| SRR2095431_GSM1816434 | RNA-Seq | 1.9 GB |
| SRR2095432 | RNA-Seq | 2.3 GB |
| SRR2095432_GSM1816434 | RNA-Seq | 2.3 GB |
| SRR2095433_GSM1816434 | RNA-Seq | 1.9 GB |
| SRR2095434_GSM1816435 | RNA-Seq | 1.9 GB |
| SRR2095435_GSM1816435 | RNA-Seq | 2.2 GB |
| SRR2095436_GSM1816435 | RNA-Seq | 1.9 GB |
| SRR2095437_GSM1816436 | RNA-Seq | 1.8 GB |
| SRR2095438_GSM1816436 | RNA-Seq | 2.1 GB |
| SRR2095439_GSM1816436 | RNA-Seq | 1.8 GB |
Potentially related datasets 5
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
| Accession | Source | Title |
|---|---|---|
| GSE28359 | GSE · GEO GEO ↗ | Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells |
| GSE24759 | GSE · GEO GEO ↗ | Densely interconnected transcriptional circuits control cell states in human hematopoiesis |
| SRP012062 | SRP · SRA | No title in the index |
| GSE69583 | GSE · GEO GEO ↗ | Musashi-2 Post-transcriptionally Attenuates Aryl Hydrocarbon Receptor Signaling to Expand Human Hematopoietic Stem Cells |
| GSE70685 | GSE · GEO GEO ↗ | Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells |
Analysis pipelines 4
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE24759 Data Processing geo_data_processing | — | 3 | GSE24759 |
| GSE28359 Data Processing geo_data_processing | — | 1 | GSE28359 |
| GSE69583 CLIP-seq Data Processing geo_data_processing | CLIP-seq | 7 | GSE69583 |
| GSE70685 RNA-seq Data Processing geo_data_processing | RNA-seq | 3 | GSE70685 |
Funding 6 grants
| Grant | Funder |
|---|---|
| R01 HG004659 | NHGRI NIH HHS (United States) |
| P41 GM103504 | NIGMS NIH HHS (United States) |
| R01 NS075449 | NINDS NIH HHS (United States) |
| HG004659 | NHGRI NIH HHS (United States) |
| MOP-126030 | Canadian Institutes of Health Research (Canada) |
| NS075449 | NINDS NIH HHS (United States) |