Autonomous silencing of the imprinted Cdkn1c gene in stem cells.
Parent-of-origin specific expression of imprinted genes relies on the differential DNA methylation of specific genomic regions. Differentially methylated regions (DMRs) acquire DNA methylation either during gametogenesis (primary DMR) or after fertilisation when allele-specific expression is established (secondary DMR). Little is known about the function of these secondary DMRs. We investigated the DMR spanning Cdkn1c in mouse embryonic stem cells, androgenetic stem cells and embryonic germ stem cells. In all cases, expression of Cdkn1c was appropriately repressed in in vitro differentiated cells. However, stem cells failed to de novo methylate the silenced gene even after sustained differentiation. In the absence of maintained DNA methylation (Dnmt1(-/-)), Cdkn1c escapes silencing demonstrating the requirement for DNA methylation in long term silencing in vivo. We propose that postfertilisation differential methylation reflects the importance of retaining single gene dosage of a subset of imprinted loci in the adult.
Wood
Michelle D
MD
Cardiff University.
Hiura
Hitoshi
H
University of Tohoku.
Tunster
Simon J
SJ
Cardiff University.
Arima
Takahiro
T
University of Tohoku.
Shin
Jong-Yeon
JY
Roswell Park Cancer Institute.
Higgins
Michael J
MJ
Roswell Park Cancer Institute.
John
Rosalind M
RM
Cardiff University.
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D018392:Genomic Imprinting; D051379:Mice
C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57