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miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on huma...

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Autores principales: Emmrich, Stephan, Rasche, Mareike, Schöning, Jennifer, Reimer, Christina, Keihani, Sarva, Maroz, Aliaksandra, Xie, Ying, Li, Zhe, Schambach, Axel, Reinhardt, Dirk, Klusmann, Jan-Henning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003278/
https://www.ncbi.nlm.nih.gov/pubmed/24736844
http://dx.doi.org/10.1101/gad.233791.113
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author Emmrich, Stephan
Rasche, Mareike
Schöning, Jennifer
Reimer, Christina
Keihani, Sarva
Maroz, Aliaksandra
Xie, Ying
Li, Zhe
Schambach, Axel
Reinhardt, Dirk
Klusmann, Jan-Henning
author_facet Emmrich, Stephan
Rasche, Mareike
Schöning, Jennifer
Reimer, Christina
Keihani, Sarva
Maroz, Aliaksandra
Xie, Ying
Li, Zhe
Schambach, Axel
Reinhardt, Dirk
Klusmann, Jan-Henning
author_sort Emmrich, Stephan
collection PubMed
description Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100∼125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor β (TGFβ) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active β-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFβ signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100∼125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.
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spelling pubmed-40032782014-10-15 miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling Emmrich, Stephan Rasche, Mareike Schöning, Jennifer Reimer, Christina Keihani, Sarva Maroz, Aliaksandra Xie, Ying Li, Zhe Schambach, Axel Reinhardt, Dirk Klusmann, Jan-Henning Genes Dev Research Paper Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100∼125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor β (TGFβ) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active β-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFβ signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100∼125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL. Cold Spring Harbor Laboratory Press 2014-04-15 /pmc/articles/PMC4003278/ /pubmed/24736844 http://dx.doi.org/10.1101/gad.233791.113 Text en © 2014 Emmrich et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Emmrich, Stephan
Rasche, Mareike
Schöning, Jennifer
Reimer, Christina
Keihani, Sarva
Maroz, Aliaksandra
Xie, Ying
Li, Zhe
Schambach, Axel
Reinhardt, Dirk
Klusmann, Jan-Henning
miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling
title miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling
title_full miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling
title_fullStr miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling
title_full_unstemmed miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling
title_short miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling
title_sort mir-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between tgfβ and wnt signaling
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003278/
https://www.ncbi.nlm.nih.gov/pubmed/24736844
http://dx.doi.org/10.1101/gad.233791.113
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