Epigenetic dynamics of theKcnq1imprinted domain in the early embryo

Abstract

The mouse Kcnq1 imprinted domain is located on distal chromosome 7 and contains several imprinted genes that are paternally repressed. Repression of these genes is regulated by a non-coding antisense transcript, Kcnq1ot1, which is paternally expressed. Maternal repression of Kcnq1ot1 is controlled by DNA methylation originating in the oocyte. Some genes in the region are imprinted only in the placenta, whereas others are imprinted in both extra-embryonic and embryonic lineages. Here, we show that Kcnq1ot1 is paternally expressed in preimplantation embryos from the two-cell stage, and that ubiquitously imprinted genes proximal to Kcnq1ot1 are already repressed in blastocysts, ES cells and TS cells. Repressive histone marks such as H3K27me3 are present on the paternal allele of these genes in both ES and TS cells. Placentally imprinted genes that are distal to Kcnq1ot1, by contrast, are not imprinted in blastocysts, ES or TS cells. In these genes, paternal silencing and differential histone marks arise during differentiation of the trophoblast lineage between E4.5 and E7.5. Our findings show that the dynamics during preimplantation development of gene inactivation and acquisition of repressive histone marks in ubiquitously imprinted genes of the Kcnq1 domain are very similar to those of imprinted X inactivation. By contrast, genes that are only imprinted in the placenta, while regulated by the same non-coding RNA transcript Kcnq1ot1, undergo epigenetic inactivation during differentiation of the trophoblast lineage. Our findings establish a model for how epigenetic gene silencing by non-coding RNA may depend on distance from the non-coding RNA and on lineage and differentiation specific factors.

Effects of maternal nutrition on the expression of genomic imprinted genes in ovine fetuses

“…Three other putative imprinted genes, SCL22A18, PHLDA2 , and KCNQ1 , are located on chromosome 21 (Figure 6) in the KCNQ1 domain, which contains several maternally expressed genes [48,49]. In our analysis, these three ovine genes also showed preferential expression from the maternal allele.…”

Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo

“…S6A) (11), which is reflected in TS and XEN cells. This contrasts, however, with postimplantation stage extraembryonic tissues, where we detected high gene-specific Kcnq1ot1 is used as a positive control (46). Mean and SD are from two biological replicates.…”

“…This would be analogous to de novo DNA methylation that occurs during preimplantation development (45). In support of this hypothesis, placentally imprinted genes acquire their differential histone marks in trophoblast between E4.5 and E7.5, and TS cells display a set of epigenetic marks before this event (46). An alternative explanation is that although global H3K27me3 is low in the extraembryonic lineages before implantation, there may still be genes marked by H3K27me3 in these tissues and these marks persist after implantation.…”

Dynamic changes in paternal X-chromosome activity during imprinted X-chromosome inactivation in mice

“…Interesting parallels can be drawn between our findings and those of imprinted clusters in which sequential and lineage-specific gene silencing linked to noncoding RNAs, such as Kcnq1ot1, have been reported. In the Kcnq1-imprinted cluster the Kcnq1ot1 RNA is paternally expressed at the 2-cell stage and is believed to participate in silencing of flanking genes on the paternal chromosome (22). It has been suggested that Kcnq1ot1 RNA represses its most proximal genes in all cells (both embryonic and extraembryonic) but that silencing spreads to more distant genes only in the trophoblast, after implantation.…”