DLEU2 encodes an antisense RNA for the putative bicistronic RFP2/LEU5 gene in humans and mouse

Abstract

Our group previously identified two novel genes, RFP2/LEU5 and DLEU2, within a 13q14.3 genomic region of loss seen in various malignancies. However, no specific inactivating mutations were found in these or other genes in the vicinity of the deletion, suggesting that a nonclassical tumor-suppressor mechanism may be involved. Here, we present data showing that the DLEU2 gene encodes a putative noncoding antisense RNA, with one exon directly overlapping the first exon of the RFP2/LEU5 gene in the opposite orientation. In addition, the RFP2/LEU5 transcript can be alternatively spliced to produce either several monocistronic transcripts or a putative bicistronic transcript encoding two separate open-reading frames, adding to the complexity of the locus. The finding that these gene structures are conserved in the mouse, including the putative bicistronic RFP2/LEU5 transcript as well as the antisense relationship with DLEU2, further underlines the significance of this unusual organization and suggests a biological function for DLEU2 in the regulation of RFP2/LEU5.

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

“…In allelic exclusion, one allele is silenced to ensure that the complex process of Ig gene recombination takes place only once. In 13q14.3, others and we observed excessive splicing of all large ncRNA genes (3,10,11). Because only genes from one of the chromosomes are expressed in 13q14.3, it is tempting to speculate that transcriptional and posttranscriptional complexity of the critical region requires silencing of the second chromosome similar to the Ig locus.…”

“…To elucidate the role of DNA methylation of CpG island E associated with the ncRNA genes in 13q14.3, we wanted to test whether methylation of DNA or acetylation of histones are involved in the silencing effects at 13q14. 3. It has been shown that treatment with inhibitors of DNA methyltransferases [e.g., 5-aza-2Ј-deoxycytidine (5-aza-CdR)] or histone deacetylases [e.g., trichostatin A (TSA)] leads to euchromatinization in cell culture (27).…”

“…However, the majority of genes localized within and in the vicinity of the critical region, including miR15 and miR16, are down-regulated in CLL with monoallelic deletions by a factor of Ͼ2, which would be expected for a simple gene-dosage effect. This substantial down-regulation upon loss of one gene copy points to an epigenetic pathomechanism (3,6,7). Intergenic regions of chromosomal band 13q14.3 are conserved in the syntenic region in mice, suggesting conservation of regulatory elements (8).…”

“…This critical region is also recurrently deleted in other hematological malignancies and a variety of solid tumors (reviewed in ref. 3). Accordingly, a tumor-suppressor mechanism has been postulated in this region.…”

Altering microRNA miR15a/16 Levels as Potential Therapy in CLL: Extrapolating from the De Novo NZB Mouse Model

“…Currently it is unclear whether the full length Dleu2 transcript is functionally important; however critical functions have been assigned to two genes encoded within Dleu2. In addition to miR15a/16-1, Dleu2 transcript also encodes an anti-sense for Dleu5 (also called Rfp2 of Trim13) (Corcoran et al, 2004). Dleu2 is transcribed from the reverse strand while Dleu5 is transcribed from the forward strand in Chr.13 in humans and Chr.14 in mice.…”