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Trisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro
Jen-Chieh Chiang1, Jun Jiang1, Peter E Newburger2
1Department of Neurology and Pediatrics, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA.
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.
Insights
Trisomy silencing using XIST in Down syndrome cells corrected blood cell overproduction. This epigenetic strategy shows promise for investigating and mitigating Down syndrome developmental disorders.
Area of Science:
- Genetics
- Developmental Biology
- Stem Cell Biology
Background:
- Down syndrome (DS) is characterized by trisomy of chromosome 21, leading to developmental abnormalities.
- Cellular phenotypes in DS are well-documented in hematopoietic stem cells.
- Previous work showed XIST transgene can repress chromosome 21 in DS pluripotent cells.
Purpose of the Study:
- To determine if trisomy silencing can normalize cell function and correct Down syndrome pathogenesis.
- To investigate the cell-type specificity of XIST-mediated trisomy silencing.
- To explore the role of trisomy 21 in hematopoietic progenitor overproduction and associated signaling pathways.
Main Methods:
- Utilized an in vitro model of human fetal hematopoiesis.
- Generated and analyzed four transgenic clones with XIST induction.
- Assessed cell production, progenitor populations (CD34+, CD43+), and IGF signaling.
Main Results:
- XIST induction in DS cells reproducibly corrected the overproduction of megakaryocytes and erythrocytes.
- Observed cell-type specific effects, with an increase in neural stem and induced pluripotent stem cells.
- Demonstrated that trisomy 21 promotes CD43+ progenitor overproduction, linked to increased IGF signaling.
Conclusions:
- Epigenetic silencing of chromosome 21 via XIST demonstrates proof-of-principle for correcting DS-associated hematopoietic pathologies.
- This approach can normalize developmental programs and rebalance cell production in DS models.
- The findings provide a strategy for investigating and potentially mitigating Down syndrome developmental disorders.
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