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. 2021 Oct 25;9:730014. doi: 10.3389/fcell.2021.730014

FIGURE 2.

FIGURE 2

Mechanisms by which imprinted lncRNA regulate allelic expression in imprinted clusters. (A) The lncRNA model of imprinted gene expression regulation. In Kcnq1ot1 imprinted cluster, the ICR is unmethylated on the paternal allele, permitting lncRNA Kcnq1ot1 expression. The expression of this lncRNA recruits the PRC1/2 complex and histone methyltransferase G9a, leading to condensed chromatin and silencing of flanking protein-coding genes. The ICR is methylated on the maternal allele, inhibiting lncRNA expression. The expression of Kcnq1 and several paternal silenced genes are activated. (B) The insulator model of imprinted gene expression regulation. The ICR on the maternal allele is unmethylated. CTCF binds to the maternal ICR and functions as an insulator to block Igf2 access to its distal enhancers. In contrast, the ICR on the paternal allele is methylated, preventing binding of CTCF. The expression of Igf2 is activated via enhancer regulation. (C) lncRNA Airn in Airn/Igf2r locus function in two distinctive mechanisms. On the one hand, methylated DMR on the maternal allele inhibits Airn expression, allowing access of transcription factors to the Igf2r promoter. The paternal DMR is unmethylated, permitting Airn transcription. Airn overlaps with the promoter of Igf2r and inhibits Igf2r expression. On the other hand, Airn transcripts recruit PRC2 complex to distal genes, such as Slc22a3 and Slc22a2, where they silence expression. Slc22a1 is a biallelic expressed protein-coding gene between distal regulated imprinted genes and Igf2r gene loci. (D) In Snurf-Snrpn/Ube3a imprinted cluster, the transcription of Ube3a-ATS starts from the exon upstream of the Snurf-Snrpn gene on the paternal allele. A group of non-coding RNAs are expressed, including Snord116 and Snord115 sno-lncRNAs and SnoRNAs. The elongation of this lncRNA overlaps with the Ube3a protein-coding region. A collision occurs between the converging elongation complexes of Ube3a-ATS and Ube3a resulting in the failure of Ube3a transcription elongation. By contrast, on the maternal allele, the ICR of Snurf-Snrpn/Ube3a cluster is methylated in the brain. G9a is recruited to the methylated DMR. This G9a accumulation leads to condensed chromatin and the silencing of flanking imprinted genes near the Snurf/Snrpn gene region. Consequently, the maternal Ube3a allele is expressed.