Yin Yang 1 is a multi-functional regulator of adipocyte differentiation in 3T3-L1 cells

Han, Younho; Choi, You Hee; Lee, Sung Ho; Jin, Yun-Hye; Cheong, Heesun; Lee, Kwang Youl

doi:10.1016/j.mce.2015.06.035

Cited by 10 publications

(7 citation statements)

References 33 publications

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“…YY1 also regulates the differentiation of muscle cells from myoblasts, in part, by repressing muscle-specific genes, such as skeletal α-actin (56), and YY1 negatively regulates Runx2 transcription, which is required for osteoblast differentiation (57). Similarly, YY1 was shown to regulate adipocyte differentiation, in that overexpression of YY1 in 3T3-L1 cells decreased differentiation and YY1 knockdown increased differentiation (58). More global gene expression analyses in cells from mice that conditionally deleted YY1 specifically in muscle cells, or in intestinal epithelial stem cells, indicated that the major pathways down-regulated in both types of knockout mice were mitochondrial bioenergetics pathways (59,60).…”

Section: Discussionmentioning

confidence: 99%

YY1 plays an essential role at all stages of B-cell differentiation

Kleiman

Jia

Loguercio

et al. 2016

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

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Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor shown to be essential for pro-B-cell development. However, the role of YY1 in other B-cell populations has never been investigated. Recent bioinformatics analysis data have implicated YY1 in the germinal center (GC) B-cell transcriptional program. In accord with this prediction, we demonstrated that deletion of YY1 by Cγ1-Cre completely prevented differentiation of GC B cells and plasma cells. To determine if YY1 was also required for the differentiation of other B-cell populations, we deleted YY1 with CD19-Cre and found that all peripheral B-cell subsets, including B1 B cells, require YY1 for their differentiation. Transitional 1 (T1) B cells were the most dependent upon YY1, being sensitive to even a half-dosage of YY1 and also to short-term YY1 deletion by tamoxifen-induced Cre. We show that YY1 exerts its effects, in part, by promoting B-cell survival and proliferation. ChIP-sequencing shows that YY1 predominantly binds to promoters, and pathway analysis of the genes that bind YY1 show enrichment in ribosomal functions, mitochondrial functions such as bioenergetics, and functions related to transcription such as mRNA splicing. By RNA-sequencing analysis of differentially expressed genes, we demonstrated that YY1 normally activates genes involved in mitochondrial bioenergetics, whereas it normally down-regulates genes involved in transcription, mRNA splicing, NF-κB signaling pathways, the AP-1 transcription factor network, chromatin remodeling, cytokine signaling pathways, cell adhesion, and cell proliferation. Our results show the crucial role that YY1 plays in regulating broad general processes throughout all stages of B-cell differentiation.YY1 | B lymphocytes | differentiation | mitochondrial bioenergetics | transcription

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Section: Discussionmentioning

confidence: 99%

YY1 plays an essential role at all stages of B-cell differentiation

Kleiman

Jia

Loguercio

et al. 2016

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

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“…Incidentally, we show that S100B/NF-κBinduced YY1 promotes myoblast-brown adipocyte transition as opposed to the inhibitory effects of YY1 on the transition of preadipocytes to white adipocytes. 54 Both microenvironmental conditions 5,6 and cell intrinsic properties [7][8][9][10][11] are responsible for the reduced myogenic potential of myofiber-associated stem cells seen in sarcopenia. A reduced ability to manage ROS appears to be one major cause of muscle wasting in elderly people [11][12][13] and, possibly, Figure 5 Chronic oxidative conditions and/or upregulation of S100B expression increase BMP-7 secretion and autocrine pro-brown adipogenic effects of BMP-7.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-κB/YY1/miR-133 axis and NF-κB/YY1/BMP-7 axis

et al. 2017

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Muscles of sarcopenic people show hypotrophic myofibers and infiltration with adipose and, at later stages, fibrotic tissue. The origin of infiltrating adipocytes resides in fibro-adipogenic precursors and nonmyogenic mesenchymal progenitor cells, and in satellite cells, the adult stem cells of skeletal muscles. Myoblasts and brown adipocytes share a common Myf5 progenitor cell: the cell fate depends on levels of bone morphogenetic protein 7 (BMP-7), a TGF-β family member. S100B, a Ca-binding protein of the EF-hand type, is expressed at relatively high levels in myoblasts from sarcopenic humans and exerts anti-myogenic effects via NF-κB-dependent inhibition of MyoD, a myogenic transcription factor acting upstream of the essential myogenic factor, myogenin. Adipogenesis requires high levels of ROS, and myoblasts of sarcopenic subjects show elevated ROS levels. Here we show that: (1) ROS overproduction in myoblasts results in upregulation of S100B levels via NF-κB activation; and (2) ROS/NF-κB-induced accumulation of S100B causes myoblast transition into brown adipocytes. S100B activates an NF-κB/Ying Yang 1 axis that negatively regulates the promyogenic and anti-adipogenic miR-133 with resultant accumulation of the brown adipogenic transcription regulator, PRDM-16. S100B also upregulates BMP-7 via NF-κB/Ying Yang 1 with resultant BMP-7 autocrine activity. Interestingly, myoblasts from sarcopenic humans show features of brown adipocytes. We also show that S100B levels and NF-κB activity are elevated in brown adipocytes obtained by culturing myoblasts in adipocyte differentiation medium and that S100B knockdown or NF-κB inhibition in myoblast-derived brown adipocytes reconverts them into fusion-competent myoblasts. At last, interstitial cells and, unexpectedly, a subpopulation of myofibers in muscles of geriatric but not young mice co-express S100B and the brown adipocyte marker, uncoupling protein-1. These results suggest that S100B is an important intracellular molecular signal regulating Myf5 progenitor cell differentiation into fusion-competent myoblasts or brown adipocytes depending on its levels.

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“…At the here identified rs7647481A nonrisk allele, proteomic analysis identified allele specific binding of two transcription factors, YY1 and NFATC4. YY1 was reported to regulate metabolic, diabetes-related phenotypes in skeletal muscle, liver and adipocytes (52–56). NFATC4 contributes to regulation of PPARG and mouse adipocyte differentiation by direct binding at the PPARG2 promoter (57), YY1 indirectly by interaction with C/EBPα (56).…”

Section: Discussionmentioning

confidence: 99%

“…YY1 was reported to regulate metabolic, diabetes-related phenotypes in skeletal muscle, liver and adipocytes (52–56). NFATC4 contributes to regulation of PPARG and mouse adipocyte differentiation by direct binding at the PPARG2 promoter (57), YY1 indirectly by interaction with C/EBPα (56). We focused on the allele-specific activity of human YY1 and found in vivo allele-specific binding at the rs7647481A nonrisk allele in the human PPARG promoter by ChIP experiments combined with assessment of allelic imbalance in heterozygous primary human adipose tissue cells, supporting the biological relevance of the proteins identified by our label-free proteomics approach.…”

Section: Discussionmentioning

confidence: 99%

Allele-specific quantitative proteomics unravels molecular mechanisms modulated by cis-regulatory PPARG locus variation

Lee

Qian

Toerne

et al. 2017

Nucleic Acids Research

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Genome-wide association studies identified numerous disease risk loci. Delineating molecular mechanisms influenced by cis-regulatory variants is essential to understand gene regulation and ultimately disease pathophysiology. Combining bioinformatics and public domain chromatin information with quantitative proteomics supports prediction of cis-regulatory variants and enabled identification of allele-dependent binding of both, transcription factors and coregulators at the type 2 diabetes associated PPARG locus. We found rs7647481A nonrisk allele binding of Yin Yang 1 (YY1), confirmed by allele-specific chromatin immunoprecipitation in primary adipocytes. Quantitative proteomics also found the coregulator RING1 and YY1 binding protein (RYBP) whose mRNA levels correlate with improved insulin sensitivity in primary adipose cells carrying the rs7647481A nonrisk allele. Our findings support a concept with diverse cis-regulatory variants contributing to disease pathophysiology at one locus. Proteome-wide identification of both, transcription factors and coregulators, can profoundly improve understanding of mechanisms underlying genetic associations.

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Yin Yang 1 is a multi-functional regulator of adipocyte differentiation in 3T3-L1 cells

Cited by 10 publications

References 33 publications

YY1 plays an essential role at all stages of B-cell differentiation

YY1 plays an essential role at all stages of B-cell differentiation

Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-κB/YY1/miR-133 axis and NF-κB/YY1/BMP-7 axis

Allele-specific quantitative proteomics unravels molecular mechanisms modulated by cis-regulatory PPARG locus variation

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