Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation.

By Marcel E. Dinger, Paulo P. Amaral, Tim R. Mercer, Ken C. Pang, Stephen J. Bruce, B. Gardiner, Marjan E Askarian-Amiri, Kelin Ru, G. Soldà, Cas Simons and 5 more. Genome Research, 2008

760 citations recorded by the source corpus.

The transcriptional networks that regulate embryonic stem (ES) cell pluripotency and lineage specification are the subject of considerable attention. To date such studies have focused almost exclusively on protein-coding transcripts. However, recent transcriptome analyses show that the mammalian genome contains thousands of long noncoding RNAs (ncRNAs), many of which appear to be expressed in a developmentally regulated manner. The functions of these remain untested. To identify ncRNAs involved in ES cell biology, we used a custom-designed microarray to examine the expression profiles of mouse ES cells differentiating as embryoid bodies (EBs) over a 16-d time course. We identified 945 ncRNAs expressed during EB differentiation, of which 174 were differentially expressed, many correlating with pluripotency or specific differentiation events. Candidate ncRNAs were identified for further characterization by an integrated examination of expression profiles, genomic context, chromatin state, and promoter analysis. Many ncRNAs showed coordinated expression with genomically associated developmental genes, such as Dlx1, Dlx4, Gata6, and Ecsit. We examined two novel developmentally regulated ncRNAs, Evx1as and Hoxb5/6as, which are derived from homeotic loci and share similar expression patterns and localization in mouse embryos with their associated protein-coding genes. Using chromatin immunoprecipitation, we provide evidence that both ncRNAs are associated with trimethylated H3K4 histones and histone methyltransferase MLL1, suggesting a role in epigenetic regulation of homeotic loci during ES cell differentiation. Taken together, our data indicate that long ncRNAs are likely to be important in processes directing pluripotency and alternative differentiation programs, in some cases through engagement of the epigenetic machinery.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0c14ecba0229664160eee4668e84737eaade78c6

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Citations in the corpus

Polycomb group proteins: navigators of lineage pathways led astray in cancer (2009, neutral): “Recently, several thousand additional long ncRNAs have been identified in both mouse and human cells, but little is known about their functio”
Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. (2012, background): “…first long noncoding transcript catalog in a vertebrate embryo and in the zebrafish—share many of the character- istics of their mammalian counterparts (Dinger et al. 2008; Guttman et al. 2009, 2010, 2011; Ponjavic et al. 2009; Cabili et al. 2011): rel- atively short length, low exon number,…”
Braveheart, a long non-coding RNA required for cardiovascular lineage commitment (2013, background): “Identification of Candidate lncRNAs in the Cardiac Lineage lncRNAs exhibit distinct expression patterns across tissues (Derrien et al., 2012; Dinger et al., 2008); however, we have limited knowledge of their precise molecular roles during mammalian development.”
Long noncoding RNAs and the genetics of cancer (2013, background): “Others bind to trithorax chromatin-activating complexes and/or activated chromatin (Dinger et al, 2008).”
Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression (2009, background): “Previous studies by us and others have demonstrated that groups of lincRNAs exhibit expression patterns across cell types and tissues that correlate with patterns seen for protein-coding genes involved in cellular processes such as cell-cycle regulation, innate immunity responses, and stem cell plur”
Large-scale prediction of long non-coding RNA functions in a coding–non-coding gene co-expression network (2011, background): “However, a number of studies have suggested that independently transcribed lncRNAs may still be co-expressed and functionally related to neighboring coding genes (11,21,40,41).”
Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci (2016, methodology): “…be induced when we differentiate NT2 cells (Figure 2C,D), similarly to the temporal co-induction seen with other coding/non-coding pairs (Supplementary Figure S5) and reminiscent of the co-regulation that we previously observed in differentiating mouse embryonic stem cells (Dinger et al., 2008).”
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Genome regulation by long noncoding RNAs (2012, background): “A similar study by this group identified numerous lncRNAs that were tightly correlated with pluripotency transcription factors suggesting that many lncRNAs may function in stem cell pluripotency transcriptional networks (73).”
Long non-coding RNAs: insights into functions (2009, background): “, and large numbers of mouse ncRNAs are specifically expressed during embryonic stem cell differentiatio”
Epigenetics and gene expression (2010, background): “Thus, in Drosophila, three lncRNAs recruit the trithorax protein Ash1 to the Ultrabithorax locus maintaining Ubx transcription (Sanchez-Elsner et al., 2006) while Dinger et al. (2008) suggest that two lncRNAs (Evx1as and Hoxb5/6as) function in a similar way in mammals.”
CpG islands and the regulation of transcription. (2011, background): “Functionally, it can be speculated that some of the transcripts initiating from gene body CGIs are regulatory ncRNAs whose presence or absence affects expression of the associated protein-coding gene or a nearby gene (Dinger et al. 2008; Mercer et al. 2009; Orom et al. 2010).”
Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB (2013, background): “Several lncRNAs exhibit temporal and spatial expression patterns or their expression is restricted to particular tissue or cell types or cell cycle stages, indicating vital and diverse biological roles of lncRNAs [4,25,26,27,28].”
Long noncoding RNAs: functional surprises from the RNA world. (2009, background): “…multiple studies have shown that significant numbers of long ncRNAs are regulated during development (Blackshaw et al. 2004; Rinn et al. 2007; Dinger et al. 2008), exhibit cell typespecific expression (Ravasi et al. 2006; Mercer et al. 2008), localize to specific subcellular compartments…”
lncRNAdb: a reference database for long noncoding RNAs (2010, background): “…several studies have documented the cell type-speciﬁc and/or dynamic expression of hundreds of long ncRNAs in various developmental systems, such as embryonic stem cell differentiation (14) and oligodendrogenesis (15), ﬁnding in each case different subsets of differentially expressed lncRNAs.”
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