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

ABSTRACT 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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Available from: Manuel Garber, Sep 26, 2015
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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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    ABSTRACT: Long noncoding (lnc)RNAs have recently emerged as key regulators of gene expression. Here, we performed high-depth poly(A)+ RNA sequencing across multiple clonal populations of mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs) to comprehensively identify differentially regulated lncRNAs. We establish a biologically robust profile of lncRNA expression in these two cell types and further confirm that the majority of these lncRNAs are enriched in the nucleus. Applying weighted gene co-expression network analysis, we define a group of lncRNAs that are tightly associated with the pluripotent state of ESCs. Among these, we show that acute depletion of PAT-14 using antisense oligonucleotides impacts the differentiation- and development-associated gene expression program of ESCs. Furthermore, we demonstrate that Firre, a lncRNA highly enriched in the nucleoplasm and previously reported to mediate chromosomal contacts in ESCs, controls a network of genes related to RNA processing. Together, we provide a comprehensive, up-to-date and high resolution compilation of lncRNA expression in ESCs and NPCs and show that nuclear lncRNAs are tightly integrated into the regulation of ESC gene expression. Published by Cold Spring Harbor Laboratory Press.
    Genome Research 06/2015; 25(9). DOI:10.1101/gr.189027.114 · 14.63 Impact Factor
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    • "Studies performed in cultured cells have implicated lncRNAs in diverse cellular processes ranging from chromatin modification, RNA stability, to translational control (Batista and Chang, 2013; Clark and Mattick, 2011). A number of reports support a prevailing mechanism for lncRNA action where lncRNAs interact with and organize histone writers, readers, and modifiers (Batista and Chang, 2013; Guttman et al., 2011) to regulate gene transcription, although it remains to be determined whether the majority of lncRNAs function through this mechanism. The physiological significance of most lncRNAs at wholeorganism level is largely unknown, although emerging reports indicate that lncRNAs could play critical roles in essential pathophysiological processes. "
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    ABSTRACT: Long non-coding RNAs (lncRNAs) constitute a significant portion of mammalian genome, yet the physiological importance of lncRNAs is largely unknown. Here, we identify a liver-enriched lncRNA in mouse that we term liver-specific triglyceride regulator (lncLSTR). Mice with a liver-specific depletion of lncLSTR exhibit a marked reduction in plasma triglyceride levels. We show that lncLSTR depletion enhances apoC2 expression, leading to robust lipoprotein lipase activation and increased plasma triglyceride clearance. We further demonstrate that the regulation of apoC2 expression occurs through an FXR-mediated pathway. LncLSTR forms a molecular complex with TDP-43 to regulate expression of Cyp8b1, a key enzyme in the bile acid synthesis pathway, and engenders an in vivo bile pool that induces apoC2 expression through FXR. Finally, we demonstrate that lncLSTR depletion can reduce triglyceride levels in a hyperlipidemia mouse model. Taken together, these data support a model in which lncLSTR regulates a TDP-43/FXR/apoC2-dependent pathway to maintain systemic lipid homeostasis. Copyright © 2015 Elsevier Inc. All rights reserved.
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