Hematopoietic precursor cells transiently reestablish permissiveness for X inactivation.
Xist is the trigger for X inactivation in female mammals. The long noncoding Xist RNA localizes along one of the two female X chromosomes and initiates chromosome-wide silencing in the early embryo. In differentiated cells, Xist becomes dispensable for the maintenance of the inactive X, and its function for initiation of silencing is lost. How Xist mediates gene repression remains an open question. Here, we use an inducible Xist allele in adult mice to identify cells in which Xist can cause chromosome-wide silencing. We show that Xist has the ability to initiate silencing in immature hematopoietic precursor cells. In contrast, hematopoietic stem cells and mature blood cells are unable to initiate ectopic X inactivation. This indicates that pathways critical for silencing are transiently activated in hematopoietic differentiation. Xist-responsive cell types in normal female mice show a change of chromatin marks on the inactive X. However, dosage compensation is maintained throughout hematopoiesis. Therefore, Xist can initiate silencing in precursors with concomitant maintenance of dosage compensation. This suggests that Xist function is restricted in development by the limited activity of epigenetic pathways rather than by a change in the responsiveness of chromatin between embryonic and differentiated cell types.
Savarese
Fabio
F
Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
Flahndorfer
Katja
K
Jaenisch
Rudolf
R
Busslinger
Meinrad
M
Wutz
Anton
A
D000483:Alleles; D000740:Anemia / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020868:Gene Silencing; D005819:Genetic Markers; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D013950:Thymus Gland / Q000166:cytology / Q000473:pathology; D049951:X Chromosome Inactivation / Q000235:genetics*
D005819:Genetic Markers; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C077885:XIST non-coding RNA