The long noncoding RNA Neat1 is required for mammary gland development and lactation

Standaert, Laura; Adriaens, Carmen; Radælli, Enrico; Keymeulen, Alexandra Van; Blanpain, Cédric; Hirose, Tetsuro; Nakagawa, Shinichi; Marine, Jean–Christophe

doi:10.1261/rna.047332.114

Cited by 170 publications

(176 citation statements)

References 21 publications

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“…While the majority of lncRNAs are expressed at low levels with tissue-specific and developmental stage-specific expression (for review, see Mercer et al 2009;Mattick 2011), the mammalian-specific lncRNA NEAT1 (nuclear paraspeckle assembly transcript 1) is ubiquitous and abundant, suggesting a more generic biological role. Importantly, NEAT1 is one of the few lncRNAs known to have a robust phenotype when knocked out in mice, in which the secretory function and the development of critical tissues relating to female reproduction are compromised Standaert et al 2014). …”

Section: Introductionmentioning

confidence: 99%

Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

Harvey

Hodgetts

et al. 2017

RNA

124

113

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Large numbers of long noncoding RNAs have been discovered in recent years, but only a few have been characterized. NEAT1 (nuclear paraspeckle assembly transcript 1) is a mammalian long noncoding RNA that is important for the reproductive physiology of mice, cancer development, and the formation of subnuclear bodies termed paraspeckles. The two major isoforms of NEAT1 (3.7 kb NEAT1_1 and 23 kb NEAT1_2 in human) are generated from a common promoter and are produced through the use of alternative transcription termination sites. This gene structure has made the functional relationship between the two isoforms difficult to dissect. Here we used CRISPR-Cas9 genome editing to create several different cell lines: total NEAT1 knockout cells, cells that only express the short form NEAT1_1, and cells with twofold more NEAT1_2. Using these reagents, we obtained evidence that NEAT1_1 is not a major component of paraspeckles. In addition, our data suggest NEAT1_1 localizes in numerous nonparaspeckle foci we termed "microspeckles," which may carry paraspeckle-independent functions. This study highlights the complexity of lncRNA and showcases how genome editing tools are useful in dissecting the structural and functional roles of overlapping transcripts.

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Section: Introductionmentioning

confidence: 99%

Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

Harvey

Hodgetts

et al. 2017

RNA

124

113

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“…These and other paraspeckle proteins sequester certain mRNA transcripts at the paraspeckle and mediate posttranscriptional splicing. While NEAT1 paraspeckles are necessary for myeloid differentiation and play a key role in mammary gland development and lactation (21), the functions of paraspeckles are still largely unknown (22).…”

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confidence: 99%

MicroRNA 140 Promotes Expression of Long Noncoding RNA NEAT1 in Adipogenesis

Gernapudi

Wolfson

Zhang

et al. 2016

Molecular and Cellular Biology

113

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More than 40% of the U.S. population are clinically obese and suffer from metabolic syndrome with an increased risk of postmenopausal estrogen receptor-positive breast cancer. Adipocytes are the primary component of adipose tissue and are formed through adipogenesis from precursor mesenchymal stem cells. While the major molecular pathways of adipogenesis are understood, little is known about the noncoding RNA signaling networks involved in adipogenesis. Using adipocyte-derived stem cells (ADSCs) isolated from wild-type and microRNA 140 (miR-140) knockout mice, we identify a novel miR-140/long noncoding RNA (lncRNA) NEAT1 signaling network necessary for adipogenesis. miR-140 knockout ADSCs have dramatically decreased adipogenic capabilities associated with downregulation of NEAT1 expression. We identified a miR-140 binding site in NEAT1 and found that mature miR-140 in the nucleus can physically interact with NEAT1, leading to increased NEAT1 expression. We demonstrated that reexpression of NEAT1 in miR-140 knockout ADSCs is sufficient to restore their ability to undergo differentiation. Our results reveal an exciting new noncoding RNA signaling network that regulates adipogenesis and that is a potential new target in the prevention or treatment of obesity. More than 40% of American adults are overweight or obese, and there are over 40 million obese women in America (1). Obese and overweight women are at greater risk for postmenopausal breast cancer and have dramatically higher rates of cancer recurrence and mortality (2, 3). Obesity is characterized by metabolic imbalance leading to adipocyte hypertrophy and hyperplasia and the excess accumulation of adipose tissue. During adipogenesis, mesenchymal stem cells (MSC) commit to the adipogenic lineage, forming proliferative, MSC-like cells called preadipocytes. By differentiating into mature adipocytes, preadipocytes replenish the nonproliferative mature adipocytes that are the bulk of white adipose tissue (4). Mature adipocytes secrete hormones and adipokines that, in addition to their metabolic function, promote breast tumor aggressiveness and invasion (5). Deciphering the mechanisms of preadipocyte differentiation and adipocyte-breast cancer cell interaction will greatly further our understanding of and our ability to treat breast cancers.MicroRNAs (miRNAs) are essential regulators of cellular function and gene expression. After nuclear processing, miRNA precursors are exported to the cytoplasm, where the mature miRNA is formed. miRNAs associate with the RNA-induced silencing complex (RISC) and base pair to seed sequences in the 3= untranslated region (UTR) of target mRNAs. This guides the RISC to the mRNA, causing degradation or inhibition of translation. miRNAs primarily function in the cytoplasm; however, some have been shown to translocate back into the nucleus and degrade nuclear RNA molecules (6). Nuclear miRNAs have also been shown to mediate mRNA upregulation by RNA activation (RNAa).

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“…Paraspeckles are ∼360 nm in diameter (8); hence, they are considered huge among RNP particles. Paraspeckles regulate the expression of a number of genes via the sequestration of specific proteins and RNAs (4,9,10), and are physiologically involved in the development of the corpus luteum and the mammary gland in mice (11,12).…”

mentioning

confidence: 99%

SWI/SNF chromatin-remodeling complexes function in noncoding RNA-dependent assembly of nuclear bodies

Kawaguchi

Tanigawa²,

Naganuma

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Paraspeckles are subnuclear structures that form around nuclear paraspeckle assembly transcript 1 (NEAT1) long noncoding RNA (lncRNA). Recently, paraspeckles were shown to be functional nuclear bodies involved in stress responses and the development of specific organs. Paraspeckle formation is initiated by transcription of the NEAT1 chromosomal locus and proceeds in conjunction with NEAT1 lncRNA biogenesis and a subsequent assembly step involving >40 paraspeckle proteins (PSPs). In this study, subunits of SWItch/Sucrose NonFermentable (SWI/SNF) chromatin-remodeling complexes were identified as paraspeckle components that interact with PSPs and NEAT1 lncRNA. EM observations revealed that SWI/SNF complexes were enriched in paraspeckle subdomains depleted of chromatin. Knockdown of SWI/SNF components resulted in paraspeckle disintegration, but mutation of the ATPase domain of the catalytic subunit BRG1 did not affect paraspeckle integrity, indicating that the essential role of SWI/SNF complexes in paraspeckle formation does not require their canonical activity. Knockdown of SWI/SNF complexes barely affected the levels of known essential paraspeckle components, but markedly diminished the interactions between essential PSPs, suggesting that SWI/SNF complexes facilitate organization of the PSP interaction network required for intact paraspeckle assembly. The interactions between SWI/SNF components and essential PSPs were maintained in NEAT1-depleted cells, suggesting that SWI/SNF complexes not only facilitate interactions between PSPs, but also recruit PSPs during paraspeckle assembly. SWI/SNF complexes were also required for Satellite III lncRNA-dependent formation of nuclear stress bodies under heat-shock conditions. Our data suggest the existence of a common mechanism underlying the formation of lncRNA-dependent nuclear body architectures in mammalian cells.chromatin-remodeling complex | long noncoding RNA | nuclear bodies | ribonucleoprotein assembly

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The long noncoding RNA Neat1 is required for mammary gland development and lactation

Cited by 170 publications

References 21 publications

Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

MicroRNA 140 Promotes Expression of Long Noncoding RNA NEAT1 in Adipogenesis

SWI/SNF chromatin-remodeling complexes function in noncoding RNA-dependent assembly of nuclear bodies

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