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Ultraconserved Sequences Associated with HoxD Cluster Have Strong Repression Activity.

ABSTRACT: Increase in the complexity of organisms during evolution strongly correlates with the increase in the noncoding DNA content of their genomes. Although a gradual increase in the proportion of repetitive DNA elements along with increasing complexity is known, most of the noncoding components of the genome remain uncharacterized. A nonrepetitive but highly conserved noncoding component of the genome in vertebrates, called ultraconserved DNA sequences, constitutes up to 5% of the human genome. The function of most of the ultraconserved DNA elements is not well known. One such ultraconserved stretch of DNA has been identified upstream of the HoxD cluster in vertebrates. We analyzed the function of these elements in different cell lines and zebrafish. Our results suggest that these ultraconserved sequences work as repressor elements. This is the first report which reveals the repressor function of ultraconserved sequences and implicates their role in the regulation of developmental genes.

SUBMITTER: Kushawah G

PROVIDER: S-EPMC5591955 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Long noncoding RNAs (lncRNAs) constitute a major, but poorly characterized part of human transcriptome. Recent evidence indicates that many lncRNAs are involved in cancer and can be used as predictive and prognostic biomarkers. Significant fraction of lncRNAs is represented on widely used microarray platforms, however they have usually been ignored in cancer studies. RESULTS: We developed a computational pipeline to annotate lncRNAs on popular Affymetrix U133 microarrays, creating a resource allowing measurement of expression of 1581 lncRNAs. This resource can be utilized to interrogate existing microarray datasets for various lncRNA studies. We found that these lncRNAs fall into three distinct classes according to their statistical distribution by length. Remarkably, these three classes of lncRNAs were co-localized with protein coding genes exhibiting distinct gene ontology groups. This annotation was applied to microarray analysis which identified a 159 lncRNA signature that discriminates between localized and metastatic stages of neuroblastoma. Analysis of an independent patient cohort revealed that this signature differentiates also relapsing from non-relapsing primary tumors. This is the first example of the signature developed via the analysis of expression of lncRNAs solely. One of these lncRNAs, termed HOXD-AS1, is encoded in HOXD cluster. HOXD-AS1 is evolutionary conserved among hominids and has all bona fide features of a gene. Studying retinoid acid (RA) response of SH-SY5Y cell line, a model of human metastatic neuroblastoma, we found that HOXD-AS1 is a subject to morphogenic regulation, is activated by PI3K/Akt pathway and itself is involved in control of RA-induced cell differentiation. Knock-down experiments revealed that HOXD-AS1 controls expression levels of clinically significant protein-coding genes involved in angiogenesis and inflammation, the hallmarks of metastatic cancer. CONCLUSIONS: Our findings greatly extend the number of noncoding RNAs functionally implicated in tumor development and patient treatment and highlight their role as potential prognostic biomarkers of neuroblastomas.

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Ultraconserved Sequences Associated with HoxD Cluster Have Strong Repression Activity.

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