Lander ES: lincRNAs act in the circuitry controlling pluripotency and differentiation

Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature (Impact Factor: 41.46). 08/2011; 477(7364):295-300. DOI: 10.1038/nature10398
Source: PubMed


Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.

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    • "Several independent studies confirmed lincRNAs to function as enhancer (eRNAs) to regulate gene expression of neighboring genes [39] [40] [41] or to act as scaffold for the recruitment of chromatin modifying enzymes to regulate the epigenetic state of specific genomic loci [42] [43] [44]. In our RNAseq analysis, we identified 89 lincRNAs to be differentially expressed in LOAD hippocampi compared to control, 72 of these are novel non-annotated RNA transcripts (Supplementary File 3). "
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    • "Despite the lack of experimental data, an altered expression pattern of the noncoding transcriptome is also expected in aging. In fact, lncRNAs are known to be involved in the control and regulation of cell fate decisions, including cell lineage commitment (Lin et al. 2014) and stemness (Guttman et al. 2011). Similar regulatory circuits based on the ncRNAs have been proposed to be on the basis of the age-dependent evolution of some human diseases such as cognitive disorders (Qureshi and Mehler 2011). "
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    Current topics in microbiology and immunology 07/2015; DOI:10.1007/82_2015_460 · 4.10 Impact Factor
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    • "We refer to these lncRNAs as Platr1 to -32 (pluripotency-associated transcript; ranked by relative module importance). Importantly, two of these lncRNAs were previously implicated in the maintenance of the ESC state: Platr11 (linc1405; Gm26975/ENSMUSG00000098161) was found to be required for Zfp42 expression (Guttman et al. 2011). Platr18 (Lincenc1; ENSMUSG00000078952) (Fig. 2A,B) was part of an early knockdown screen and is critically necessary for ESC colony formation (Ivanova et al. 2006). "
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