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Multi-dimensional conservation analysis reveals transcriptional codes ruling the expression of conserved long noncoding RNAs

ABSTRACT: Although long non-coding RNAs (lncRNAs) encounter weaker evolutionary constraints and exhibit lower sequences conservation than coding genes, lncRNAs can conserve their features at different aspects. Here, we employed multiple approaches to systemically evaluate the conservation between human and mouse lncRNAs from various dimensions including sequences, promoter, global synteny, and local synteny, which led to the identification of 1731 conserved lncRNAs with 427 ultraconserved ones meeting multiple criteria. The conserved lncRNAs, in comparison with non-conserved ones, in generally have longer gene bodies, higher numbers of exons and transcripts, closer connections with human diseases, and are more abundant and widespread across different tissues. The transcriptional factor profile analysis revealed a significant enrichment of TF types and numbers in the promoters of conserved lncRNAs. We further identified a set of TFs that preferentially bind to conserved lncRNAs and exert stronger impacts on their expression than non-conserved lncRNAs’ expression. Thus, our study has revealed a new set of transcriptional “codes” that rules the expression of the conserved lncRNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156270 | GEO | 2023/03/19

REPOSITORIES: GEO

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Project description:Mammals express thousands of long noncoding (lnc) RNAs, a few of which are shown to function in tissue development. However, the entire repertoire of lncRNAs and the extent to which they regulate biological processes in different tissues and species are not defined. Indeed, most lncRNAs are not conserved between species, raising questions about function. We used RNA-Seq to identify lncRNAs in primary murine fetal liver erythroblasts expressing the lineage marker TER119, megakaryocytes (CD41+) cultured from embryonic day (E) 14.5 murine fetal liver and megakaryocyte erythroid progenitors (MEPs) isolated from mouse bone marrow. We identified 683 and 594 polyadenylated lncRNAs expressed in red blood cell (erythroid) precursors of mice and humans, respectively. More than one half of erythroid lncRNAs are un-annotated, emphasizing the opportunity for new discovery through studies of specialized cell types. We analyzed the expression of these identified lncRNAs in several hematopoietic compartments using a custom microarray to identify erythroid-specific lncRNAs that were robustly expressed in both fetal liver and adult erythroid cells as targets for knockdown. Over 90% of fetal liver erythroid lncRNAs detected using RNA-seq were expressed in adult erythroblasts measured on the microarray. Analysis of the murine erythroid lncRNA transcriptome indicates that ~75% arise from promoters and 25% from enhancers, many of which are regulated by the key erythroid transcription factors GATA1 and SCL/TAL1. Erythroid lncRNA expression is largely conserved among 8 different mouse strains, yet only 15% of mouse lncRNAs are expressed in humans and vice versa, reflecting dramatically greater species-specificity than coding genes. We investigated potential functions of 21 relatively abundant erythroid-specific murine lncRNAs (both conserved and non-conserved) by RNA interference in primary mouse erythroid precursors, and identified 7 whose knockdown inhibited features of terminal erythroid maturation including cell size reduction and enucleation. Strikingly, at least 6 of the 7 lncRNAs have no detectable expression in human erythroblasts, demonstrating that lack of conservation between mammalian species does not predict lack of function. These results reflect marked evolutionary differences between protein-coding genes and lncRNAs and indicate that the latter exert tissue- and species-specific roles in development. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf A custom Agilent microarray was designed to interrogate expression levels of long noncoding RNAs identified using RNA-seq in several different hematopoietic progenitor and differentiated cell populations. LncRNA gene definitions and RNA-seq data used to identify long noncoding RNAs are deposited in GEO with the accession numbers GSE51667 and GSE40522 respectively. The Agilent eArray platform was used to customize the SurePrint G3 Mouse GE 8x60K microarray to add 3 custom-designed probes (60nt length) each against several categories of genes, namely pseudogene, genes with small RNA overlap, low stringency lncRNAs and high stringency lncRNAs . We interrogated 7 types of hematopoietic cells, HSC, CMP, MEP, GMP, early and late erythroblasts and granulocytes. Expression measurements were determined at least in duplicate for all samples and in triplicate for most samples.

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Multi-dimensional conservation analysis reveals transcriptional codes ruling the expression of conserved long noncoding RNAs

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