Chromatin dynamics during epigenetic reprogramming in the mouse germ line.
A unique feature of the germ cell lineage is the generation of totipotency. A critical event in this context is DNA demethylation and the erasure of parental imprints in mouse primordial germ cells (PGCs) on embryonic day 11.5 (E11.5) after they enter into the developing gonads. Little is yet known about the mechanism involved, except that it is apparently an active process. We have examined the associated changes in the chromatin to gain further insights into this reprogramming event. Here we show that the chromatin changes occur in two steps. The first changes in nascent PGCs at E8.5 establish a distinctive chromatin signature that is reminiscent of pluripotency. Next, when PGCs are residing in the gonads, major changes occur in nuclear architecture accompanied by an extensive erasure of several histone modifications and exchange of histone variants. Furthermore, the histone chaperones HIRA and NAP-1 (NAP111), which are implicated in histone exchange, accumulate in PGC nuclei undergoing reprogramming. We therefore suggest that the mechanism of histone replacement is critical for these chromatin rearrangements to occur. The marked chromatin changes are intimately linked with genome-wide DNA demethylation. On the basis of the timing of the observed events, we propose that if DNA demethylation entails a DNA repair-based mechanism, the evident histone replacement would represent a repair-induced response event rather than being a prerequisite.
Hajkova
Petra
P
Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
Ancelin
Katia
K
Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
Waldmann
Tanja
T
Max-Planck-Institute of Immunobiology, Stuebeweg 51, 79108 Freiburg, Germany.
Lacoste
Nicolas
N
CNRS/Institute Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Lange
Ulrike C
UC
Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
Cesari
Francesca
F
Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
Lee
Caroline
C
Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
Almouzni
Genevieve
G
CNRS/Institute Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Schneider
Robert
R
Max-Planck-Institute of Immunobiology, Stuebeweg 51, 79108 Freiburg, Germany.
Surani
M Azim
MA
Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005854:Germ Cells / Q000378:metabolism*; D006066:Gonads / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D013234:Stem Cells / Q000378:metabolism
D002843:Chromatin; D006657:Histones