scholarly journals GPS2 regulates mitochondria biogenesis via mitochondrial retrograde signaling and chromatin remodeling of nuclear-encoded mitochondrial genes

2017 ◽  
Author(s):  
Maria Dafne Cardamone ◽  
Bogdan Tanasa ◽  
Carly Cederquist ◽  
Jiawen Huang ◽  
Kiana Mahdaviani ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Mitochondrial Gene ◽  
Nuclear Gene ◽  
Mitochondrial Genes ◽  
Retrograde Signaling ◽  
Gene Promoters ◽  
Brown Adipose ◽  
Mitochondrial Functions ◽  
Mitochondrial Retrograde Signaling

SummaryAs most of the mitochondrial proteome is encoded in the nucleus, mitochondrial functions critically depend on nuclear gene expression and bidirectional mito-nuclear communication. However, mitochondria-to-nucleus communication pathways are incompletely understood. Here, we identify G-Protein Pathway Suppressor 2 (GPS2) as a mediator of mitochondrial retrograde signaling and a key transcriptional activator of nuclear-encoded mitochondrial genes in mammals. GPS2 regulated translocation from mitochondria to nucleus is essential for the transcriptional activation of the nuclear stress response to mitochondrial depolarization and for supporting basal mitochondrial biogenesis in differentiating adipocytes and in brown adipose tissue from mice. In the nucleus, GPS2 recruitment to target gene promoters regulates histone H3K9 demethylation and RNA Polymerase II (POL2) activation through inhibition of Ubc13-mediated ubiquitination. Together, these findings reveal an unexpected layer of regulation of mitochondrial gene transcription as they uncover a novel mitochondria-nuclear communication pathway.

scholarly journals Enhanced osteoclastogenesis by mitochondrial retrograde signaling through transcriptional activation of the cathepsin K gene

2015 ◽  
Vol 1364 (1) ◽  
pp. 52-61 ◽  
Author(s):  
Manti Guha ◽  
Satish Srinivasan ◽  
Alexander Koenigstein ◽  
Mone Zaidi ◽  
Narayan G. Avadhani
Keyword(s):  
Transcriptional Activation ◽  
Cathepsin K ◽  
Retrograde Signaling ◽  
Mitochondrial Retrograde Signaling

Translational regulation of mitochondrial gene expression by nuclear genes of Saccharomyces cerevisiae

1988 ◽  
Vol 319 (1193) ◽  
pp. 97-105 ◽  
Keyword(s):  
Gene Expression ◽  
Mitochondrial Gene ◽  
Nuclear Gene ◽  
Mitochondrial Genes ◽  
Nuclear Genes ◽  
Mitochondrial Gene Expression ◽  
Wild Type ◽  
Mitochondrial Translation ◽  
Coding Sequence ◽  
Sites Of Action

We describe several yeast nuclear mutations that specifically block expression of the mitochondrial genes encoding cytochrome c oxidase subunits II (COXII) and III (COXIII). These recessive mutations define positive regulators of mitochondrial gene expression that act at the level of translation. Mutations in the nuclear gene PET111 completely block accumulation of COXII, but the COXII mRNA is present in mutant cells at a level approximately one-third of that of the wild type. Mitochondrial suppressors of pet 111 mutations correspond to deletions in mtDNA that result in fusions between the cox II structural gene and other mitochondrial genes. The chimeric mRNAs encoded by these fusions are translated in pet 111 mutants; this translation leads to accumulation of functional COXII. The PET111 protein probably acts directly on cox II translation, because it is located in mitochondria. Translation of the mitochondrially coded mRNA for COXIII requires the action of at least three nuclear genes, PET 494, and a newly discovered gene, provisionally termed PET 55. Both the PET494 and PET54 proteins are located in mitochondria and therefore probably act directly on the mitochondrial translation system. Mutations in all three genes are suppressed in strains that contain chimeric cox III mRNAs with the 5'-untranslated leaders of other mitochondrial transcripts fused to the cox III coding sequence. The products of all three nuclear genes may form a complex and carry out a single function. A direct demonstration that the wild-type nuclear gene products act in the cox III 5'-leader has been obtained by showing that they are all required for translation of apocytochrome b from a novel mRNA consisting of the cox lIl 5'-leader attached to the cytochrome b coding sequence. The site (or sites) of action maps at least 172 bases upstream from the cox lll initiation codon in the 600 base cox III leader. Others have reported evidence which suggests that cox Ill translation is repressed by glucose. Consistently with the possibility that the nuclear genes described here may play a role in modulating mitochondrial gene expression, we have found that PET 494 expression is glucose-repressed.

scholarly journals Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study

2021 ◽  
Vol 27 ◽  
Author(s):  
Baojin Wu ◽  
Xinjie Tang ◽  
Honglin Ke ◽  
Qiong Zhou ◽  
Zhaoping Zhou ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Adrenocortical Carcinoma ◽  
Mitochondrial Gene ◽  
Disease Free Survival ◽  
Mitochondrial Genes ◽  
Lower Grade ◽  
Hippo Signaling ◽  
Hub Genes ◽  
Human Cancers ◽  
Mitochondrial Functions

Background: Yes-associated protein 1 (YAP1) is the main downstream effector of the Hippo signaling pathway, which is involved in tumorigenesis. This study aimed to comprehensively understand the prognostic performances of YAP1 expression and its potential mechanism in pan-cancers by mining databases.Methods: The YAP1 expression was evaluated by the Oncomine database and GEPIA tool. The clinical significance of YAP1 expression was analyzed by the UALCAN, GEPIA, and DriverDBv3 database. Then, the co-expressed genes with YAP1 were screened by the LinkedOmics, and annotated by the Metascape and DAVID database. Additionally, by the MitoMiner 4.0 v tool, the YAP1 co-expressed genes were screened to obtain the YAP1-associated mitochondrial genes that were further enriched by DAVID and analyzed by MCODE for the hub genes.Results: YAP1 was differentially expressed in human cancers. Higher YAP1 expression was significantly associated with poorer overall survival and disease-free survival in adrenocortical carcinoma (ACC), brain Lower Grade Glioma (LGG), and pancreatic adenocarcinoma (PAAD). The LinkedOmics analysis revealed 923 co-expressed genes with YAP1 in adrenocortical carcinoma, LGG and PAAD. The 923 genes mainly participated in mitochondrial functions including mitochondrial gene expression and mitochondrial respiratory chain complex I assembly. Of the 923 genes, 112 mitochondrial genes were identified by MitoMiner 4.0 v and significantly enriched in oxidative phosphorylation. The MCODE analysis identified three hub genes including CHCHD1, IDH3G and NDUFAF5.Conclusion: Our findings showed that the YAP1 overexpression could be a biomarker for poor prognosis in ACC, LGG and PAAD. Specifically, the YAP1 co-expression genes were mainly involved in the regulation of mitochondrial function especially in oxidative phosphorylation. Thus, our findings provided evidence of the carcinogenesis of YAP1 in human cancers and new insights into the mechanisms underlying the role of YAP1 in mitochondrial dysregulation.

scholarly journals Polycomb regulation is coupled to cell cycle transition in pluripotent stem cells

2020 ◽  
Author(s):  
Helena G. Asenjo ◽  
Amador Gallardo ◽  
Lourdes López-Onieva ◽  
Irene Tejada ◽  
Jordi Martorell-Marugán ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Differentiation ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Embryonic Stem ◽  
Gene Promoters ◽  
Polycomb Repressive Complex 2 ◽  
Cell Cycle Transition ◽  
Target Promoters

SummaryWhen self-renewing pluripotent cells receive a differentiation signal, ongoing cell duplication needs to be coordinated with entry into a differentiation program. Accordingly, transcriptional activation of lineage specifiers genes and cell differentiation is confined to the G1-phase of the cell cycle by unknown mechanisms. We found that Polycomb repressive complex 2 (PRC2) subunits are differentially recruited to lineage specifier gene promoters across cell cycle in mouse embryonic stem cells (mESCs). Jarid2 and the catalytic subunit Ezh2 are dramatically accumulated at target promoters during S and G2, while the transcriptionally activating subunits EPOP and EloB are enriched during G1. Importantly, fluctuations in the recruitment of PRC2 subunits promote changes in RNA synthesis and RNA polymerase II binding that are compromised in Jarid2 -/- mESCs. Overall, we show that differential recruitment of PRC2 subunits across cell cycle enables the establishment of a chromatin state that facilitates the induction of cell differentiation in G1.

scholarly journals HnRNPA2 is a novel histone acetyltransferase that mediates mitochondrial stress-induced nuclear gene expression

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Manti Guha ◽  
Satish Srinivasan ◽  
Kip Guja ◽  
Edison Mejia ◽  
Miguel Garcia-Diaz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mitochondrial Dna ◽  
Transcriptional Activation ◽  
Nuclear Gene ◽  
C2c12 Cells ◽  
Retrograde Signaling ◽  
Epigenetic Mechanism ◽  
Mitochondrial Stress ◽  
Nuclear Gene Expression ◽  
Mitochondrial Dna Copy Number

Abstract Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced transcription coactivator hnRNAP2 acetylates Lys 8 of H4 through an intrinsic histone lysine acetyltransferase (KAT) activity with Arg 48 and Arg 50 of hnRNAP2 being essential for acetyl-CoA binding and acetyltransferase activity. H4K8 acetylation at the mitochondrial stress-responsive promoters by hnRNAP2 is essential for transcriptional activation. We found that the previously described mitochondria-to-nucleus retrograde signaling-mediated transformation of C2C12 cells caused an increased expression of genes involved in various oncogenic processes, which is retarded in hnRNAP2 silenced or hnRNAP2 KAT mutant cells. Taken together, these data show that altered gene expression by mitochondria-to-nucleus retrograde signaling involves a novel hnRNAP2-dependent epigenetic mechanism that may have a role in cancer and other pathologies.

scholarly journals Product of Saccharomyces cerevisiae nuclear gene PET494 activates translation of a specific mitochondrial mRNA.

1986 ◽  
Vol 6 (11) ◽  
pp. 3694-3703 ◽  
Author(s):  
M C Costanzo ◽  
T D Fox
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Fusion Protein ◽  
Mitochondrial Gene ◽  
Nuclear Gene ◽  
Mitochondrial Genes ◽  
Wild Type ◽  
Site Of Action ◽  
Flanking Sequences ◽  
Untranslated Leaders ◽  
Beta Galactosidase

The product of Saccharomyces cerevisiae nuclear gene PET494 is known to be required for a posttranscriptional step in the accumulation of one mitochondrial gene product, subunit III of cytochrome c oxidase (coxIII). Here we show that the PET494 protein probably acts in mitochondria by demonstrating that both a PET494-beta-galactosidase fusion protein and unmodified PET494 are specifically associated with mitochondria. To define the PET494 site of action, we isolated mutations that suppress a pet494 deletion. These mutations were rearrangements of the mitochondrial gene oxi2 that encodes coxIII. The suppressor oxi2 genes had acquired the 5'-flanking sequences of other mitochondrial genes and gave rise to oxi2 transcripts carrying the 5'-untranslated leaders of their mRNAs. These results demonstrate that in wild-type cells PET494 specifically promotes coxIII translation, probably by interacting with the 5'-untranslated leader of the oxi2 mRNA.

scholarly journals Sub1 Functions in Osmoregulation and in Transcription by both RNA Polymerases II and III

2009 ◽  
Vol 29 (8) ◽  
pp. 2308-2321 ◽  
Author(s):  
Emanuel Rosonina ◽  
Ian M. Willis ◽  
James L. Manley
Keyword(s):  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Chromatin Immunoprecipitation ◽  
Osmotic Shock ◽  
Gene Promoters ◽  
Hog Pathway ◽  
General Role ◽  
High Osmolarity Glycerol ◽  
Rnap Ii ◽  
Insight Into

ABSTRACT Sub1 is implicated in transcriptional activation, elongation, and mRNA 3′-end formation in budding yeast. To gain more insight into its function, we performed a synthetic genetic array screen with SUB1 that uncovered genetic interactions with genes involved in the high-osmolarity glycerol (HOG) osmoresponse pathway. We find that Sub1 and the HOG pathway are redundant for survival in moderate osmolarity. Chromatin immunoprecipitation analysis shows that Sub1 is recruited to osmoresponse gene promoters during osmotic shock and is required for full recruitment of TBP, TFIIB, and RNA polymerase II (RNAP II) at a subset of these genes. Furthermore, we detect Sub1 at the promoter of every constitutively transcribed RNAP II and, unexpectedly, at every RNAP III gene tested, but not at the RNAP I-transcribed ribosomal DNA promoter. Significantly, deletion of SUB1 reduced levels of promoter-associated RNAP II or III at these genes, but not TBP levels. Together these data suggest that, in addition to a general role in polymerase recruitment at constitutive RNAP II and RNAP III genes, during osmotic shock, Sub1 facilitates osmoresponse gene transcription by enhancing preinitiation complex formation.

scholarly journals Genome-Wide Association of Mediator and RNA Polymerase II in Wild-Type and Mediator Mutant Yeast

2014 ◽  
Vol 35 (1) ◽  
pp. 331-342 ◽  
Author(s):  
Emily Paul ◽  
Z. Iris Zhu ◽  
David Landsman ◽  
Randall H. Morse
Keyword(s):  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Open Reading Frames ◽  
Temperature Sensitive ◽  
Gene Promoters ◽  
Content Type ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range

Mediator is a large, multisubunit complex that is required for essentially all mRNA transcription in eukaryotes. In spite of the importance of Mediator, the range of its targets and how it is recruited to these is not well understood. Previous work showed that inSaccharomyces cerevisiae, Mediator contributes to transcriptional activation by two distinct mechanisms, one depending on the tail module triad and favoring SAGA-regulated genes, and the second occurring independently of the tail module and favoring TFIID-regulated genes. Here, we use chromatin immunoprecipitation sequencing (ChIP-seq) to show that dependence on tail module subunits for Mediator recruitment and polymerase II (Pol II) association occurs preferentially at SAGA-regulated over TFIID-regulated genes on a genome-wide scale. We also show that recruitment of tail module subunits to active gene promoters continues genome-wide when Mediator integrity is compromised inmed17temperature-sensitive (ts) yeast, demonstrating the modular nature of the Mediator complexin vivo. In addition, our data indicate that promoters exhibiting strong and stable occupancy by Mediator have a wide range of activity and are enriched for targets of the Tup1-Cyc8 repressor complex. We also identify a number of strong Mediator occupancy peaks that overlap dubious open reading frames (ORFs) and are likely to include previously unrecognized upstream activator sequences.

Classical and Novel TSPO Ligands for the Mitochondrial TSPO can Modulate Nuclear Gene Expression: Implicationsfor Mitochondrial Retrograde Signaling

2016 ◽  
Author(s):  
Nasra Yasin ◽  
Leo Veenman ◽  
Maya Azrad ◽  
Alex Vainshtein ◽  
Bea Caballero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Gene ◽  
Retrograde Signaling ◽  
Nuclear Gene Expression ◽  
Mitochondrial Retrograde Signaling

scholarly journals TBP Dynamics in Living Human Cells: Constitutive Association of TBP with Mitotic Chromosomes

2002 ◽  
Vol 13 (1) ◽  
pp. 276-284 ◽  
Author(s):  
Danyang Chen ◽  
Craig S. Hinkley ◽  
R. William Henry ◽  
Sui Huang
Keyword(s):  
Rna Polymerase Ii ◽  
Dynamic Behavior ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Green Fluorescence Protein ◽  
Gene Promoters ◽  
Mitotic Chromosomes ◽  
General Transcription Factor ◽  
Rate Limiting Step ◽  
Fluorescence Protein

The recruitment of TATA binding protein (TBP) to gene promoters is a critical rate-limiting step in transcriptional regulation for all three eukaryotic RNA polymerases. However, little is known regarding the dynamics of TBP in live mammalian cells. In this report, we examined the distribution and dynamic behavior of green fluorescence protein (GFP)-tagged TBP in live HeLa cells using fluorescence recovery after photobleaching (FRAP) analyses. We observed that GFP-TBP associates with condensed chromosomes throughout mitosis without any FRAP. These results suggest that TBP stably associates with the condensed chromosomes during mitosis. In addition, endogenous TBP and TBP-associated factors (TAFs), specific for RNA polymerase II and III transcription, cofractionated with mitotic chromatin, suggesting that TBP is retained as a TBP-TAF complex on transcriptionally silent chromatin throughout mitosis. In interphase cells, GFP-TBP distributes throughout the nucleoplasm and shows a FRAP that is 100-fold slower than the general transcription factor GFP-TFIIB. This difference supports the idea that TBP and, most likely, TBP-TAF complexes, remain promoter- bound for multiple rounds of transcription. Altogether, our observations demonstrate that there are cell cycle specific characteristics in the dynamic behavior of TBP. We propose a novel model in which the association of TBP-TAF complexes with chromatin during mitosis marks genes for rapid transcriptional activation as cells emerge from mitosis.

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