MicroRNA-26 Family Is Required for Human Adipogenesis and Drives Characteristics of Brown Adipocytes

Karbiener, Michael; Pisani, Didier F.; Frontini, Andrea; Oberreiter, Lisa Maria; Lang, Eleonore; Vegiopoulos, Alexandros; Mössenböck, Karin; Bernhardt, Gerwin A.; Mayr, Torsten; Hildner, Florian; Grillari, Johannes; Ailhaud, Gérard; Herzig, Stephan; Cinti, Saverio; Amri, Ez-Zoubir; Scheideler, Marcel

doi:10.1002/stem.1603

Cited by 148 publications

(152 citation statements)

References 76 publications

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“…Increases in myomiR-1 and other miRNAs, including miR-455 and -26, were highly correlated with BA-specific proteins in differentiating BAs in the present and previous studies. 27,37 For instance, expression profiles of miR-1/206 and miR-133 were highly correlated with the MEF2C protein during myogenesis, 38,39 and the upregulated MEF2C in turn initiated expression of miR-1 at early stage of myogenesis by binding to the intragenic of miR-1-2 cluster. 39 miR-1 and -133 were often generated together from 2 bicistronic clusters but execute opposite functions during the Figure 6.…”

Section: Discussionmentioning

confidence: 99%

RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes

Lin

2015

RNA Biology

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Keywords: alternative splicing, brown adipocytes, MEF2C, miR-1, RBM4Myocyte enhancer factor 2c (MEF2C) is the MADS-box type transcription factor involved in the differentiation of cardiac and skeletal muscle and synaptic formation. Alternatively spliced transcripts of the MEF2C gene were proven to encode isoforms which exert distinct functions in transcriptional regulation. During the differentiation of brown adipocytes, upregulated RBM4 enhanced skipping of the MEF2Cg region which functions as a transcriptional repressor. The presence of an overexpressed MEF2Cg-isoform in turn induced transcriptional activity of the RBM4 promoter, constituting a positive feedback circuit in differentiating brown adipocytes. The RBM4-MEF2Cg-network induced the expression of "myogenic" miR-1 to a greater extent than did PRDM17, BMP7 C/EBPb, or UCP1 transcripts in C3H10T1/2 cells. Overexpression of miR-1 independently exerted the same activity as RBM4 and the MEF2Cg-isoform of upregulating brown adipocyte-specific factors in C3H10T1/2 cells, which suggests a potential effect of miR-1 on brown adipocytes. These results indicated that the RBM4-MEF2C-miR-1 network constitutes a novel mechanism which programs the gene expression profile toward the development of brown adipocytes.

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Section: Discussionmentioning

confidence: 99%

RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes

Lin

2015

RNA Biology

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“…57 It has been reported that the miR-26 family are involved in human adipogenesis. 49 , 22 More importantly, the miR-26a/b are expressed concomitantly with their host genes in GMEC. Our data revealed a functional significance between miR-26a/b and the CTDSP family in the regulation of lipid metabolism in GMEC, which is consistent with the effect on human adipogenesis 22 , 48 and in cell cycle control.…”

Section: Discussionmentioning

confidence: 99%

“…49 , 22 More importantly, the miR-26a/b are expressed concomitantly with their host genes in GMEC. Our data revealed a functional significance between miR-26a/b and the CTDSP family in the regulation of lipid metabolism in GMEC, which is consistent with the effect on human adipogenesis 22 , 48 and in cell cycle control. 5 The expression of PPARG is essential for fat cell differentiation and normal lipid metabolism in adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the miR-26 family is involved in adipocyte development and the acquisition of brown adipocyte characteristics in humans. 22 The genomic loci of miR-26a and miR-26b are localized in the introns of genes encoding the protein family C-terminal domain RNA polymerase Ⅱpolypeptide A small phosphatase (CTDSP). Transcription of miR-26a and miR-26b occurs via three genomic loci, miR-26a-1, miR-26a-2 and miR26b, which reside in the introns of genes coding for CTDSPL, CTDSP2 and CTDSP1, respectively.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting theINSIG1gene

et al. 2016

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The microRNA-26 (miR-26) family is known to control adipogenesis in non-ruminants. The genomic loci of miR-26a and miR-26b have been localized in the introns of genes encoding for the proteins of the Cterminal domain RNA polymerase II polypeptide A small phosphatase (CTDSP) family. Insulin-induced gene 1 (INSIG1) encodes a protein with a key role in the regulation of lipogenesis in rodent liver. In the present study, we investigated the synergistic function of the miR-26 family and their host genes in goat mammary epithelial cells (GMEC). Downregulation of miR-26a/b and their host genes in GMEC decreased the expression of genes relate to fatty acid synthesis (PPARG, LXRA, SREBF1, FASN, ACACA, GPAM, LPIN1, DGAT1 and SCD1), triacylglycerol accumulation and unsaturated fatty acid synthesis. Luciferase reporter assays confirmed INSIG1 as a direct target of miR-26a/b. Furthermore, inhibition of the CTDSP family also downregulated the expression of INSIG1. Taken together, our findings highlight a functional association of miR-26a/b, their host genes and INSIG1, and provide new insights into the regulatory network controlling milk fat synthesis in GMEC. The data indicate that targeting this network via nutrition might be important for regulating milk fat synthesis in ruminants.

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“…Several miRNAs have been found to play important regulatory roles in either promoting (miR-140, miR-26a/b, and miR-455) (11,12) or suppressing (miR-27 and miR-133) adipogenesis (13,14). miR-140 is an important regulator of developmental pathways and stem cell differentiation and is a tumor suppressor in breast cancer (15)(16)(17).…”

mentioning

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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MicroRNA-26 Family Is Required for Human Adipogenesis and Drives Characteristics of Brown Adipocytes

Cited by 148 publications

References 76 publications

RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes

RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes

MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting theINSIG1gene

MicroRNA 140 Promotes Expression of Long Noncoding RNA NEAT1 in Adipogenesis

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