UMMS Affiliation

Department of Neurology; Department of Pediatrics, Division of Hematology Oncology; Lawrence Lab

Publication Date

2018-12-05

Document Type

Article

Disciplines

Cell Biology | Cells | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Biology | Genetic Phenomena | Hematology | Hemic and Immune Systems | Hemic and Lymphatic Diseases | Nervous System Diseases | Neurology

Abstract

We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. XIST induction in four transgenic clones reproducibly corrected over-production of megakaryocytes and erythrocytes, key to DS myeloproliferative disorder and leukemia. A contrasting increase in neural stem and iPS cells shows cell-type specificity, supporting this approach successfully rebalances the hematopoietic developmental program. Given this, we next used this system to extend knowledge of hematopoietic pathogenesis on multiple points. Results demonstrate trisomy 21 expression promotes over-production of CD43(+) but not earlier CD34(+)/CD43(-)progenitors and indicates this is associated with increased IGF signaling. This study demonstrates proof-of-principle for this epigenetic-based strategy to investigate, and potentially mitigate, DS developmental pathologies.

Keywords

XIST, Down syndrome, trisomy-silencing, hematopoiesis, cell development

Rights and Permissions

Copyright © The Author(s) 2018. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1038/s41467-018-07630-y

Source

Nat Commun. 2018 Dec 5;9(1):5180. doi: 10.1038/s41467-018-07630-y. Link to article on publisher's site

Journal/Book/Conference Title

Nature communications

Related Resources

Link to Article in PubMed

PubMed ID

30518921

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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