Long non-coding RNA identification over mouse brain development by integrative modeling of chromatin and genomic features

Abstract

In silico prediction of genomic long non-coding RNAs (lncRNAs) is prerequisite to the construction and elucidation of non-coding regulatory network. Chromatin modifications marked by chromatin regulators are important epigenetic features, which can be captured by prevailing high-throughput approaches such as ChIP sequencing. We demonstrate that the accuracy of lncRNA predictions can be greatly improved when incorporating high-throughput chromatin modifications over mouse embryonic stem differentiation toward adult Cerebellum by logistic regression with LASSO regularization. The discriminating features include H3K9me3, H3K27ac, H3K4me1, open reading frames and several repeat elements. Importantly, chromatin information is suggested to be complementary to genomic sequence information, highlighting the importance of an integrated model. Applying integrated model, we obtain a list of putative lncRNAs based on uncharacterized fragments from transcriptome assembly. We demonstrate that the putative lncRNAs have regulatory roles in vicinity of known gene loci by expression and Gene Ontology enrichment analysis. We also show that the lncRNA expression specificity can be efficiently modeled by the chromatin data with same developmental stage. The study not only supports the biological hypothesis that chromatin can regulate expression of tissue-specific or developmental stage-specific lncRNAs but also reveals the discriminating features between lncRNA and coding genes, which would guide further lncRNA identifications and characterizations.

Long Non-coding RNAs: key players in brain and central nervous system development

“…The results together with others (Lv et al, 2013a;Lv et al, 2013b;Ng et al, 2012b;Qureshi and Mehler, 2012) have highlighted the importance of lncRNAs in regulation of cellular fate in neural cells and brain. Increasing evidences suggested that lncRNAs can control epigenetic targeting via their ability to bind RNA, DNA and protein (Guttman and Rinn, 2012;Mercer and Mattick, 2013;Tsai et al, 2010).…”

“…Actually, many transcriptomic studies have revealed the dynamic lncRNA expression profiles and their functions among developing, fetal and adult tissues, in additional to embryonic stem (ES) cells Sheik Mohamed et al, 2010), neural cell subtypes Aprea et al, 2013;Lin et al, 2011), and brain Ponjavic et al, 2009;Lv et al, 2013a;Lv et al, 2013b).…”

Databases for lncRNAs: a comparative evaluation of emerging tools

“…Indeed, a nuclear isoform of PTEN antisense transcript and its cytosolic counterparts have opposite effects on PTEN expression, due to differential sequestration of small ncRNAs within the two cellular compartments (Poliseno et al 2010;Jalali et al 2012). Owing to these diverse molecular mechanisms, lncRNAs are now known as important regulators of fundamental processes such as development, imprinting, and cell differentiation (Kretz 2013;Lee and Bartolomei 2013;Lv et al 2013). They are also involved in stress responses to heat, hypoxia, or DNA damage (Jolly et al 2004;Bertozzi et al 2011;Wu et al 2012;Place and Noonan 2013;Wan et al 2013;Yang et al 2013a;Zhang et al 2013).…”

Identification and analysis of mouse non-coding RNA using transcriptome data

“…Previous studies indicated that both protein-coding genes and non-coding genes were associated with diverse chromatin signals Lv et al, 2013). H3K4me3 and H3K27me3 are known to mark promoters for activating and repressing gene expression respectively (Li et al, 2012), while H3K36me3 generally marks the elongation sites of transcribed regions (Lv et al, 2013).…”

“…H3K4me3 and H3K27me3 are known to mark promoters for activating and repressing gene expression respectively (Li et al, 2012), while H3K36me3 generally marks the elongation sites of transcribed regions (Lv et al, 2013). So we examined these related transcriptional element of all non-coding RNAs.…”