Defective Mitochondrial Morphology and Bioenergetic Function in Mice Lacking the Transcription Factor Yin Yang 1 in Skeletal Muscle

Manganese (Mn)-induced neurotoxicity resembles Parkinson's disease (PD), but the mechanisms underpinning its effects remain unknown. Mn dysregulates astrocytic glutamate transporters, GLT-1 and GLAST, and dopaminergic function, including tyrosine hydroxylase (TH). Our previous in vitro studies have shown that Mn repressed GLAST and GLT-1 via activation of transcription factor Yin Yang 1 (YY1). Here, we investigated if in vivo astrocytic YY1 deletion mitigates Mn-induced dopaminergic neurotoxicity, attenuating Mn-induced reduction in GLAST/GLT-1 expression in murine substantia nigra (SN). AAV5-GFAP-Cre-GFP particles were infused into the SN of 8-week–old YY1flox/flox mice to generate a region-specific astrocytic YY1 conditional knockout (cKO) mouse model. 3 weeks after adeno-associated viral (AAV) infusion, mice were exposed to 330 μg of Mn (MnCl2 30 mg/kg, intranasal instillation, daily) for 3 weeks. After Mn exposure, motor functions were determined in open-field and rotarod tests, followed by Western blotting, quantitative PCR, and immunohistochemistry to assess YY1, TH, GLAST, and GLT-1 levels. Infusion of AAV5-GFAP-Cre-GFP vectors into the SN resulted in region-specific astrocytic YY1 deletion and attenuation of Mn-induced impairment of motor functions, reduction of TH-expressing cells in SN, and TH mRNA/protein levels in midbrain/striatum. Astrocytic YY1 deletion also attenuated the Mn-induced decrease in GLAST/GLT-1 mRNA/protein levels in midbrain. Moreover, YY1 deletion abrogated its interaction with histone deacetylases in astrocytes. These results indicate that astrocytic YY1 plays a critical role in Mn-induced neurotoxicity in vivo, at least in part, by reducing astrocytic GLAST/GLT-1. Thus, YY1 might be a potential target for treatment of Mn toxicity and other neurological disorders associated with dysregulation of GLAST/GLT-1.

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Repression of the Steroidogenic Acute Regulatory Gene by the Multifunctional Transcription Factor Yin Yang 1

Endocrinology ◽

10.1210/endo.143.3.8668 ◽

2002 ◽

Vol 143 (3) ◽

pp. 1085-1096 ◽

Cited By ~ 23

Author(s):

Anna C. Nackley ◽

Wendy Shea-Eaton ◽

Dayami Lopez ◽

Mark P. McLean

Keyword(s):

Transcription Factor ◽

Regulatory Gene ◽

Yin Yang 1 ◽

Yin Yang ◽

Steroidogenic Acute Regulatory ◽

Multifunctional Transcription Factor

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Inhibition of the transcription factor Yin Yang 1 activity by S-nitrosation

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2005.08.150 ◽

2005 ◽

Vol 336 (2) ◽

pp. 692-701 ◽

Cited By ~ 58

Author(s):

Fumiya Hongo ◽

Hermes Garban ◽

Sara Huerta-Yepez ◽

Mario Vega ◽

Ali R. Jazirehi ◽

...

Keyword(s):

Transcription Factor ◽

Yin Yang 1 ◽

Yin Yang

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Regulation of Transcription Factor Yin Yang 1 by SET7/9-mediated Lysine Methylation

Scientific Reports ◽

10.1038/srep21718 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 16

Author(s):

Wen-juan Zhang ◽

Xiao-nan Wu ◽

Tao-tao Shi ◽

Huan-teng Xu ◽

Jia Yi ◽

...

Keyword(s):

Transcription Factor ◽

Regulation Of Transcription ◽

Lysine Methylation ◽

Yin Yang 1 ◽

Yin Yang

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Essential Dosage-Dependent Functions of the Transcription Factor Yin Yang 1 in Late Embryonic Development and Cell Cycle Progression

Molecular and Cellular Biology ◽

10.1128/mcb.26.9.3565-3581.2006 ◽

2006 ◽

Vol 26 (9) ◽

pp. 3565-3581 ◽

Cited By ~ 119

Author(s):

El Bachir Affar ◽

Frédérique Gay ◽

Yujiang Shi ◽

Huifei Liu ◽

Maite Huarte ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Transcription Factor ◽

Cell Cycle Progression ◽

Target Genes ◽

Eukaryotic Cell ◽

Dependent Manner ◽

Phenotypic Analysis ◽

Yin Yang 1 ◽

Yin Yang

ABSTRACT Constitutive ablation of the Yin Yang 1 (YY1) transcription factor in mice results in peri-implantation lethality. In this study, we used homologous recombination to generate knockout mice carrying yy1 alleles expressing various amounts of YY1. Phenotypic analysis of yy1 mutant embryos expressing ∼75%, ∼50%, and ∼25% of the normal complement of YY1 identified a dosage-dependent requirement for YY1 during late embryogenesis. Indeed, reduction of YY1 levels impairs embryonic growth and viability in a dose-dependent manner. Analysis of the corresponding mouse embryonic fibroblast cells also revealed a tight correlation between YY1 dosage and cell proliferation, with a complete ablation of YY1 inducing cytokinesis failure and cell cycle arrest. Consistently, RNA interference-mediated inhibition of YY1 in HeLa cells prevents cytokinesis, causes proliferative arrest, and increases cellular sensitivity to various apoptotic agents. Genome-wide expression profiling identified a plethora of YY1 target genes that have been implicated in cell growth, proliferation, cytokinesis, apoptosis, development, and differentiation, suggesting that YY1 coordinates multiple essential biological processes through a complex transcriptional network. These data not only shed new light on the molecular basis for YY1 developmental roles and cellular functions, but also provide insight into the general mechanisms controlling eukaryotic cell proliferation, apoptosis, and differentiation.

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Expression, Activity, and Subcellular Localization of the Yin Yang 1 Transcription Factor inXenopusOocytes and Embryos

Journal of Biological Chemistry ◽

10.1074/jbc.m011188200 ◽

2001 ◽

Vol 276 (25) ◽

pp. 22819-22825 ◽

Cited By ~ 26

Author(s):

Andrew Ficzycz ◽

Christopher Eskiw ◽

Danielle Meyer ◽

Kate Eliassen Marley ◽

Myra Hurt ◽

...

Keyword(s):

Transcription Factor ◽

Subcellular Localization ◽

Yin Yang 1 ◽

Yin Yang ◽

Expression Activity

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Transcriptional regulation of human abraxas brother protein 1 expression by yin yang 1

Biochemistry and Cell Biology ◽

10.1139/bcb-2019-0279 ◽

2020 ◽

Author(s):

Pan Song ◽

Jian Hong ◽

Yuan Wang ◽

Xuelian Yao ◽

Yiqun Zhan ◽

...

Keyword(s):

Transcription Factor ◽

Transcriptional Regulation ◽

Transcriptional Start Site ◽

Regulatory Elements ◽

Start Codon ◽

Mobility Shift ◽

Cis Acting ◽

Yin Yang 1 ◽

Activating Transcription Factor 4 ◽

Yin Yang

Abraxas brother protein 1 (ABRO1) is a subunit of the deubiquitinating enzyme BRCC36-containing isopeptidase complex and plays important roles in cellular responses to stress by interacting with its binding partners, such as ubiquitin-specific peptidase 7, p53, activating transcription factor 4, THAP-domain containing 5, and serine hydroxymethyltransferase. However, the transcriptional regulation of ABRO1 remains unexplored. In this study, we identified and characterized the core regulatory elements of the human ABRO1 gene and mapped them to the ABRO1 promoter region. Additionally, 5′ rapid amplification of cDNA ends revealed that the transcriptional start site (TSS) was located −13 bp upstream from the start codon. Reporter gene, chromatin immunoprecipitation, and electrophoretic mobility shift assays demonstrated that ABRO1 transcription was regulated through cis-acting elements located in the region −89 to −59 bp upstream of the ABRO1 TSS and that these elements were targeted by yin yang 1 transcription factor (YY1). Moreover, YY1 overexpression increased human ABRO1 mRNA and protein expression, and small-interfering RNA-mediated downregulation of YY1 attenuated ABRO1 expression. These results suggested that YY1 positively regulated human ABRO1 expression by binding to cis-acting elements located in the ABRO1 TSS.

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