While “the rule of three” principle may make three the magic number for fairy tales and Hollywood blockbusters, trisomy of chromosome 21 causes Down syndrome (DS) and leads to the development of a range of severe associated disease and disorders in affected patients. However, research out of the laboratory of Jeanne B. Lawrence (University of Massachusetts Medical School, USA) now suggests that the reversal of DS-associated hematopoietic defects may be just an epigenetic switch away thanks to long non-coding (lnc)RNA.
Previously, the Lawrence lab succeeded in epigenetically silencing gene expression on one copy of chromosome 21 in DS induced pluripotent stem cells (DS-iPSCs) by engineering the specific expression of the X-inactive specific transcript (XIST) lncRNA, which normally functions in X chromosome inactivation, from one chromosome 21. Now, the group return with the next chapter in this story; a study that assesses whether epigenetic trisomy silencing by their lncRNA “switch” can reverse DS-associated hematopoietic abnormalities in an in vitro model of human fetal hematopoiesis.
Let’s take a look at this exciting study from Chiang and colleagues in more detail:
- Inducible XIST transgene expression from a single locus on a single copy of chromosome 21 in DS-iPSCs enhances proliferation and boosts neural progenitor formation, thereby highlighting a beneficial role for this lncRNA
- XIST transgene
expression also rebalances the abnormal hematopoietic developmental program
- XIST transgene expression and trisomy silencing reverses the megakaryocyte and erythrocyte over-production known to occur during DS-associated myeloproliferative disorder and leukemia
- The authors
also employed their in vitro
iPSC-based system and XIST-mediated trisomy silencing to explore the hematopoietic abnormalities observed in DS patients more
- Trisomy of chromosome 21 promotes the over-production of CD43+ hematopoietic progenitors emerging from the endothelial-to-hematopoietic transition, but not earlier CD34+/CD43- progenitors
- This CD34+ hematopoietic progenitor over-production also causes the previously observed megakaryocyte and erythrocyte over-production
- Further research highlighted increased insulin growth factor signaling as the cause of hematopoietic progenitor over-production
Overall, these findings demonstrate how an epigenetic switch can successfully reverse DS-associated hematopoietic abnormalities by suppressing gene expression from the extra copy of chromosome 21. Furthermore, these promising findings firmly established the XIST lncRNA transgene as a potential basis of a novel and effective therapeutic strategy for DS-associated disease.