By contrast, loss of the H3K9methyltransferase EHMT2 affects impr

By contrast, loss of the H3K9methyltransferase EHMT2 affects imprinted expression of EXEL genes only [ 30]. Although a direct connection has not been shown, these results imply that the Kcnq1ot1 ncRNA product targets repressive chromatin modifying complexes to imprinted genes in extra-embryonic tissues causing silencing. A recent study reported that RNAi knockdown of Kcnq1ot1

in embryonic (ES), trophoblast (TS) and extra-embryonic CP-868596 cell line endoderm (XEN) stem cells had no effect on the maintenance of imprinted expression raising the possibility that the ncRNA product plays no role in silencing [ 26]. However these results need to accommodate the finding that Kcnq1ot1 is a nuclear localised ncRNA and it is uncertain if RNAi can act in the mammalian nucleus [ 27 and 31]. The concept that

transcription, rather than the macro ncRNA product, may regulate overlapped imprinted genes is emerging for the Igf2r, Gnas, and Copg2 imprinted gene clusters. Transcriptional interference, where one transcriptional process interferes with another without the involvement of a mature RNA, is a well-established cis-silencing mechanism in non-mammalian organisms like bacteria, yeast, and Drosophila, and has been suggested to occur in mammals [ 32••]. In both the Igf2r and the Gnas clusters, the macro ncRNA overlaps the promoter of a protein-coding gene in an antisense orientation. Truncation of the macro ncRNAs Airn and Nespas, so that

however the Igf2r and Nesp promoters are not overlapped, respectively, leads to a loss of repression of both protein-coding genes, indicating that repression may result from transcriptional interference; however, these data do not exclude a role for the ncRNA product [ 6, 7•• and 33]. In the Copg2 cluster, alternative polyadenylation of the paternally expressed Mest gene produces a longer form of this gene called MestXL, specifically in the mouse nervous system. MestXL overlaps the 3′ end of Copg2 in antisense orientation correlating with paternal repression of Copg2, and this repression is lost when MestXL is truncated [ 34]. This result shows that variants of protein-coding genes can also act like macro ncRNAs to regulate other genes, and was interpreted as silencing by transcriptional interference, which would indicate that transcription across the promoter is not required. However, truncation experiments do not exclude a role for the ncRNA product in silencing, as both transcription and the ncRNA product are lost downstream of the truncation site. In the case of Airn, two aspects of its RNA biology, a short half-life and inefficient splicing [ 23], make it less likely that the mature ncRNA product is involved in silencing Igf2r in the embryo.

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