A Runx2-HDAC1 co-repressor complex regulates rRNA gene expression by modulating UBF acetylation

Ali, S.; Dobson, Jason R.; Lian, Jane B.; Stein, Janet L.; Wijnen, André J. van; Zaidi, Sayyed K.

doi:10.1242/jcs.100909

Cited by 37 publications

(40 citation statements)

References 60 publications

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“…Moreover, SIRT1 levels are reduced in breast cancer and in hepatocellular carcinoma (187). One report demonstrated that HDAC1-mediated deacetylation of H3K9 and histone H4 at the rDNA promoter suppresses rRNA transcription by RUNX2, a factor that controls bone lineage commitment and cell proliferation, in human cancer osteosarcoma cells (190).…”

Section: Disease Progressionmentioning

confidence: 99%

The Epigenetic Pathways to Ribosomal DNA Silencing

Srivastava

Ahn

2016

Microbiol Mol Biol Rev

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SUMMARYHeterochromatin is the transcriptionally repressed portion of eukaryotic chromatin that maintains a condensed appearance throughout the cell cycle. At sites of ribosomal DNA (rDNA) heterochromatin, epigenetic states contribute to gene silencing and genome stability, which are required for proper chromosome segregation and a normal life span. Here, we focus on recent advances in the epigenetic regulation of rDNA silencing inSaccharomyces cerevisiaeand in mammals, including regulation by several histone modifications and several protein components associated with the inner nuclear membrane within the nucleolus. Finally, we discuss the perturbations of rDNA epigenetic pathways in regulating cellular aging and in causing various types of diseases.

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Section: Disease Progressionmentioning

confidence: 99%

The Epigenetic Pathways to Ribosomal DNA Silencing

Srivastava

Ahn

2016

Microbiol Mol Biol Rev

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“…Additionally, RUNX2 protein is shown to be a component of the nuclear matrix and to act as a nuclear scaffolding factor (1,9,10). We asked if the local chromatin state is altered at the Runx2-P1 and Supt3h promoter regions during differentiation, in which the looping intensity is significantly increased upon differentiation.…”

Section: Resultsmentioning

confidence: 99%

The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter

Barutcu

Tai

et al. 2014

Nucleic Acids Research

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Three-dimensional organization of chromatin is fundamental for transcriptional regulation. Tissue-specific transcriptional programs are orchestrated by transcription factors and epigenetic regulators. The RUNX2 transcription factor is required for differentiation of precursor cells into mature osteoblasts. Although organization and control of the bone-specific Runx2-P1 promoter have been studied extensively, long-range regulation has not been explored. In this study, we investigated higher-order organization of the Runx2-P1 promoter during osteoblast differentiation. Mining the ENCODE database revealed interactions between Runx2-P1 and Supt3h promoters in several non-mesenchymal human cell lines. Supt3h is a ubiquitously expressed gene located within the first intron of Runx2. These two genes show shared synteny across species from humans to sponges. Chromosome conformation capture analysis in the murine pre-osteoblastic MC3T3-E1 cell line revealed increased contact frequency between Runx2-P1 and Supt3h promoters during differentiation. This increase was accompanied by enhanced DNaseI hypersensitivity along with RUNX2 and CTCF binding at the Supt3h promoter. Furthermore, interplasmid-3C and luciferase reporter assays showed that the Supt3h promoter can modulate Runx2-P1 activity via direct association. Taken together, our data demonstrate physical proximity between Runx2-P1 and Supt3h promoters, consistent with their syntenic nature. Importantly, we identify the Supt3h promoter as a potential regulator of the bone-specific Runx2-P1 promoter.

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“…These results may be a consequence of weak Runx2 interaction at a single site or possibly epitope masking due to the formation of a Runx2 multimeric complex with co-regulatory factors. Large Runx2 complexes can include histone modifying enzymes, co-activators and co-repressors, and other co-regulators associated with cancer, such as AP-1, c-myc, p53, mediators of src signaling, HOXa10, PBX, WWOX, TLE and ETS-1 [Ali et al, 2012; Aqeilan et al, 2007; Gordon et al, 2010; Pratap et al, 2011; Schroeder et al, 2005; Yang et al, 2001; Yang et al, 2010]. Thus, although a Runx2 ChIP could not detect Runx2 binding to IL-11, all other evidences [Bamba et al, 2003] strongly indicate Runx2 regulation via Runx2-Smad complexes at SBEs.…”

Section: Discussionmentioning

confidence: 99%

Expression of the IL‐11 Gene in Metastatic Cells Is Supported by Runx2‐Smad and Runx2‐cJun Complexes Induced by TGFβ1

Zhang

Dobson

et al. 2015

J of Cellular Biochemistry

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In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes in IL-11 expression. The IL-11 gene has Runx2, AP-1 sites and Smad binding elements located on the IL-11 promoter. Here, we demonstrated that Runx2-c-Jun as well as Runx2-Smad complexes upregulate IL-11 expression. Functional studies identified a significant loss of IL-11 expression in PC3 cells in the presence of the Runx2-HTY mutant protein, a mutation that disrupts Runx2-Smad signaling. In response to TGFβ1 and in the presence of Runx2, we observed a 30-fold induction of IL-11 expression, accompanied by increased c-Jun binding to the IL-11 promoter. Immunoprecipitation and in situ co-localization studies demonstrated that Runx2 and c-Jun form nuclear complexes in PC3 cells. Thus, TGFβ1 signaling induces two independent transcriptional pathways - AP-1 and Runx2. These transcriptional activators converge on IL-11 as a result of Runx2-Smad and Runx2-c-Jun interactions to amplify IL-11 gene expression that, together with Runx2, supports the osteolytic pathology of cancer induced bone disease.

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A Runx2-HDAC1 co-repressor complex regulates rRNA gene expression by modulating UBF acetylation

Cited by 37 publications

References 60 publications

The Epigenetic Pathways to Ribosomal DNA Silencing

The Epigenetic Pathways to Ribosomal DNA Silencing

The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter

Expression of the IL‐11 Gene in Metastatic Cells Is Supported by Runx2‐Smad and Runx2‐cJun Complexes Induced by TGFβ1

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