AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans

Abstract

The human genome, like other mammalian genomes, encodes numerous natural antisense transcripts (NATs) that have been classified into head-to-head, tail-to-tail, or fully overlapped categories in reference to their sense transcripts. Evidence for NAT-mediated epigenetic silencing of sense transcription remains scanty. The DHRS4 gene encodes a metabolic enzyme and forms a gene cluster with its two immediately downstream homologous genes, DHRS4L2 and DHRS4L1 , generated by gene duplication. We identified a head-to-head NAT of DHRS4 , designated AS1DHRS4, which markedly regulates the expression of these three genes in the DHRS4 gene cluster. By pairing with ongoing sense transcripts, AS1DHRS4 not only mediates deacetylation of histone H3 and demethylation of H3K4 in cis for the DHRS4 gene, but also interacts physically in trans with the epigenetic modifiers H3K9- and H3K27-specific histone methyltransferases G9a and EZH2, targeting the promoters of the downstream DHRS4L2 and DHRS4L1 genes to induce local repressive H3K9me2 and H3K27me3 histone modifications. Furthermore, AS1DHRS4 induces DNA methylation in the promoter regions of DHRS4L2 by recruiting DNA methyltransferases. This study demonstrates that AS1DHRS4, as a long noncoding RNA, simultaneously controls the chromatin state of each gene within the DHRS4 gene cluster in a discriminative manner. This finding provides an example of transcriptional control over the multiple and highly homologous genes in a tight gene cluster, and may help explain the role of antisense RNAs in the regulation of duplicated genes as the result of genomic evolution.

Interethnic DNA Methylation Difference and Its Implications in Pharmacoepigenetics

“…However, the two promoter E-CpGs displayed straightforward relationships between their higher average methylation levels and their lower average expression levels of long noncoding RNA DHRS4-AS1 through negative CorMG in the AA population (Supplementary Table 6D). DHRS4-AS1 induces the promoter methylation of DHRS4 and silences DHRS4 expression [46]. Therefore, our result reflects the previous finding and further shows its interethnic difference.…”

Long Noncoding RNA GAPLINC Regulates CD44-Dependent Cell Invasiveness and Associates with Poor Prognosis of Gastric Cancer

“…The lncRNA expression microarray used in this study mainly classifies its probes as the following subtypes: (i) enhancer LncRNAs: contain profiling data of all LncRNAs with enhancer-like function (19). (ii) Rinn lincRNAs: contain profiling data of all lincRNAs based on John Rinn's articles (20,21). (iii) HOX cluster: contains profiling data of all probes in the four HOX loci, targeting 407 discrete transcribed regions, lncRNAs, and coding transcripts (22).…”

“…Although a small number of lncRNAs have been functionally characterized (14)(15)(16)(17), a large number of members in the class remain functionally uncharacterized (18,19). Growing evidence suggests that cancer lncRNAs, similar to PCGs, may mediate oncogenic or tumor-suppressing effects and may be a new class of cancer biomarkers and therapeutic targets (20)(21)(22). One such lncRNA is HOTAIR, which is expressed from the developmental HOXC locus and associates with chromatin modifications in cooperation with the Polycomb complex PRC2 (23).…”

Functional Crosstalk Between Lysine Methyltransferases on Histone Substrates: The Case of G9A/GLP and Polycomb Repressive Complex 2

“…The imprinted-monoallelically expressed lncRNA Air regulates G9a targeting, inducing the epigenetic allelespecific silencing of the cis-linked Slc22a3, Slc22a2, and Igf2r genes in mouse placenta (93). Interestingly, two different lncRNAs have been shown to bind G9a and PRC2, Kcnqot1 (105) and AS1DHRS4 (76) Despite a unifying view on PRC2/G9a/GLP recruitment being still missing, the evidences described earlier point toward a multi-step process, which might comprise a combination of the different mechanisms, thereby ensuring a tight and dynamic regulation of PRC2 and G9a/GLP chromatin targeting.…”