Abstract
Long noncoding RNAs (lncRNAs) have been shown to play important roles in gene regulatory networks acting in early development. There has been rapid turnover of lncRNA loci during vertebrate evolution, with few human lncRNAs conserved beyond mammals. The sequences of these rare deeply conserved lncRNAs are typically not similar to each other. Here, we characterize HOXA-AS3 and HOXB-AS3, lncRNAs produced from the central regions of the HOXA and HOXB clusters. Sequence-similar orthologs of both lncRNAs are found in multiple vertebrate species and there is evident sequence similarity between their promoters, suggesting that the production of these lncRNAs predates the duplication of the HOX clusters at the root of the vertebrate lineage. This conservation extends to similar expression patterns of the two lncRNAs, in particular in cells transiently arising during early development or in the adult colon. Functionally, the RNA products of HOXA-AS3 and HOXB-AS3 regulate the expression of their overlapping HOX5-7 genes both in HT-29 cells and during differentiation of human embryonic stem cells. Beyond production of paralogous protein-coding and microRNA genes, the regulatory program in the HOX clusters therefore also relies on paralogous lncRNAs acting in restricted spatial and temporal windows of embryonic development and cell differentiation.
Highlights
Over the past decade, genome-wide transcriptome analyses revealed a plaetora of noncoding RNAs, that are expressed from a large number of genomic loci
We characterize in detail two long noncoding RNAs (lncRNAs), HOXA-AS3 and HOXB-AS3, which are transcribed from matching regions in the HOXA and HOXB clusters, respectively
Conserved and cis-acting lncRNAs produced from paralogous regions in the of HOXA and HOXB clusters expression of HOXA-AS3 and HOXB-AS3 is likely driven by conserved and shared binding sites for CDX transcription factors in the HOXA-AS3 and HOXB-AS3 promoters
Summary
Genome-wide transcriptome analyses revealed a plaetora of noncoding RNAs, that are expressed from a large number of genomic loci. Among those non-coding genes are long noncoding RNAs (lncRNAs), RNA Pol products that are longer than 200 nt. To mRNAs, lncRNAs begin with a 5’ cap and end with a poly(A) tail. Many lncRNAs display highly restricted expression profiles during development, potentially allowing them to control gene expression in specific cellular contexts [2,3]. Some lncRNAs have been shown to contribute to proper embryonic development [4]
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