@article{e91399560d094fb4a84bb2c7cb15f628,
title = "Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation",
abstract = "Naive human embryonic stem cells (hESCs) can be derived from primed hESCs or directly from blastocysts, but their X chromosome state has remained unresolved. Here, we show that the inactive X chromosome (Xi) of primed hESCs was reactivated in naive culture conditions. Like cells of the blastocyst, the resulting naive cells contained two active X chromosomes with XIST expression and chromosome-wide transcriptional dampening and initiated XIST-mediated X inactivation upon differentiation. Both establishment of and exit from the naive state (differentiation) happened via an XIST-negative XaXa intermediate. Together, these findings identify a cell culture system for functionally exploring the two X chromosome dosage compensation processes in early human development: X dampening and X inactivation. However, remaining differences between naive hESCs and embryonic cells related to mono-allelic XIST expression and non-random X inactivation highlight the need for further culture improvement. As the naive state resets Xi abnormalities seen in primed hESCs, it may provide cells better suited for downstream applications.",
keywords = "X chromosome, X chromosome dampening, X chromosome inactivation, XIST, embryonic stem cells, human development, human stem cells, lncRNA, naive pluripotency, pluripotent stem cells",
author = "Anna Sahakyan and Rachel Kim and Constantinos Chronis and Shan Sabri and Giancarlo Bonora and Theunissen, {Thorold W.} and Edward Kuoy and Justin Langerman and Clark, {Amander T.} and Rudolf Jaenisch and Kathrin Plath",
note = "Funding Information: We are grateful to Jinghua Tang, Iris Dror, Jacques Serizay, Yihao Yang, Sanjeet Patel, and Xu Qian for help with experiments. We thank Bill Lowry and Austin Smith for reagents. A.S. was supported by the Ruth L. Kirschstein NRSA F31 Fellowship (GM115122), the Iris Cantor-UCLA Women's Health Center Award (UCLA CTSI UL1TR000124), the Philip Whitcome Pre-Doctoral Fellowship, and the Mangasar M. Mangasarian Scholarship; C.C. by a CIRM Training Grant and a Leukemia and Lymphoma Research Visiting Fellowship (10040); R.K. and S.S. by the UCLA Broad Stem Cell Center and the Rose Hills Foundation; G.B. by the Philip Whitcome Pre-doctoral Fellowship, the UCLA Dissertation Year Fellowship, and the UCLA Quantitative and Computational Biosciences Postdoctoral Fellowship; T.W.T. by a Sir Henry Wellcome Postdoctoral Fellowship (098889/Z/12/Z); A.T.C. by NIH HD079546; R.J. by NIH grants R01-CA084198 and 2R01MH104610; and K.P. by the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, the UCLA David Geffen School of Medicine, the Jonsson Comprehensive Cancer Center, CIRM (RB-06133 and RB3-05080), the Iris Cantor Award (UCLA CTSI UL1TR000124), and NIH P01 GM099134. No federal grant funding was used for work with human embryos or derivation of new hESC lines. No payment was provided to embryo donors for their generous contribution to stem cell research. Publisher Copyright: {\textcopyright} 2017",
year = "2017",
month = jan,
day = "5",
doi = "10.1016/j.stem.2016.10.006",
language = "English",
volume = "20",
pages = "87--101",
journal = "Cell Stem Cell",
issn = "1934-5909",
number = "1",
}