Dataset Information

REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice.

ABSTRACT: In mice, imprinted X-chromosome inactivation (iXCI) of the paternal X in the pre-implantation embryo and extra-embryonic tissues is followed by X-reactivation in the epiblast precursors of the inner cell mass (ICM) of the blastocyst, to facilitate initiation of random XCI (rXCI) in all embryonic tissues. RNF12 is an E3 ubiquitin-ligase that plays a key role in XCI. RNF12 targets pluripotency protein REX1 for degradation to initiate rXCI in embryonic stem cells (ESCs) and loss of the maternal copy of Rnf12 leads to embryonic lethality due to iXCI failure. Here, we show that loss of Rex1 rescues the rXCI phenotype observed in Rnf12-/- ESCs, and that REX1 is the prime target of RNF12 in ESCs. Genetic ablation of Rex1 in Rnf12-/- mice rescues the Rnf12-/- iXCI phenotype, and results in viable and fertile Rnf12-/-:Rex1-/- female mice displaying normal iXCI and rXCI. Our results show that REX1 is the critical target of RNF12 in XCI.

INSTRUMENT(S): LTQ Orbitrap, Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Jeroen Demmers

LAB HEAD: Jeroen Demmers

PROVIDER: PXD010944 | Pride | 2018-11-15

REPOSITORIES: Pride

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REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice.

Gontan Cristina C Mira-Bontenbal Hegias H Magaraki Aristea A Dupont Catherine C Barakat Tahsin Stefan TS Rentmeester Eveline E Demmers Jeroen J Gribnau Joost J

Nature communications 20181112 1

In mice, imprinted X chromosome inactivation (iXCI) of the paternal X in the pre-implantation embryo and extraembryonic tissues is followed by X reactivation in the inner cell mass (ICM) of the blastocyst to facilitate initiation of random XCI (rXCI) in all embryonic tissues. RNF12 is an E3 ubiquitin ligase that plays a key role in XCI. RNF12 targets pluripotency protein REX1 for degradation to initiate rXCI in embryonic stem cells (ESCs) and loss of the maternal copy of Rnf12 leads to embryonic ...[more]

PMID: 30420655

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Project description:B-type lamins, the major structural component of the nuclear lamina, is thought to play a repressive role in the expression of many of its bound genes whose silencing are known to be critical for cell differentiation during early development. Using global mapping of lamin-B-chromatin interaction, we find that the binding to lamin-B indeed correlated with gene silencing in mouse embryonic stem cells (ESC) and ESC-derived trophectoderm (TE) lineage cells. To address whether lamin-B directly suppresses the expression of the bound genes, we have derived ESCs from lamin-B-null mouse blastocysts. Unexpectedly, microarray analyses of ESCs and TE cells show that B-type lamins do not repress the expression of their bound genes. Furthermore, the knockout mice that do not express any B-type lamins can develop to term but exhibit small body size and perinatal lethality. Our studies demonstrate that B-type lamins are not required for cell differentiation during early embryonic development. Instead, they are required for proper late embryonic and perinatal development. The availability of the null ESCs and mice opens the door to further define the functions of B-type lamins. The Dam and Dam-lamin B1 (Lmnb1) lentivirus generated from 293T cells were concentrated by spinning at 25,000 rpm with the SW28Ti rotor (Beckman) for 3 hours. The viral pellets were resuspended in 1x PBS. For ESCs, freshly trypsinized ESCs were plated into a 6-well plate with 2 ml complete GMEM medium containing either Dam or Dam-Lmnb1 lentivirus, spin-infected at 700g for 45 min, and incubated for a total of 48 hours. For TE cells, TSCs were differentiated toward TE cells for 6 days. On day 6, the TE cells were transduced by spin-infection as above with a fresh TS medium containing either Dam or Dam-Lmnb1 lentivirus. The TE cells were incubated for 48 hours after viral transduction. The adenine-methylated DNAs were amplified from the genomic DNA by adaptor-mediated PCR. The amplified DNAs were labeled by the Dual color DNA labeling kit (Roche). The labeled DNAs were hybridized with 2.1M mouse whole-genome tiling arrays (NimbleGen, 05327911001), which covers non-repetitive regions in approximately 250 bp intervals, according to the manufacturer's recommendation. This submission represents the gene expression component of the study.

Dataset Information

REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice.

Publications

REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice.

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