Secondary DNA structure formation for Hoxb9 promoter and identification of its specific binding protein

Yamagishi, Takumi; Hirose, Shigehisa; Kondo, Takashi

doi:10.1093/nar/gkm1079

Cited by 11 publications

(9 citation statements)

References 29 publications

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“…Based on these observations, and considering that KDM2B also encodes a ZF-CxxC domain, we set out to examine whether KDM2B had a similar role to KDM2A in binding non-methylated DNA and CGIs (Blackledge et al, 2010). In agreement with previous work, recombinant KDM2B was found to bind non-methylated DNA in vitro (Koyama-Nasu et al, 2007; Yamagishi et al, 2008; Blackledge et al, 2012) in a manner that is comparable to that of KDM2A (Figure 1A,B). This suggests that KDM2B, like KDM2A, may recognize non-methylated DNA in vivo and bind CGI elements.…”

Section: Resultssupporting

confidence: 92%

KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands

Farcas

Blackledge

Sudbery

et al. 2012

eLife

423

507

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CpG islands (CGIs) are associated with most mammalian gene promoters. A subset of CGIs act as polycomb response elements (PREs) and are recognized by the polycomb silencing systems to regulate expression of genes involved in early development. How CGIs function mechanistically as nucleation sites for polycomb repressive complexes remains unknown. Here we discover that KDM2B (FBXL10) specifically recognizes non-methylated DNA in CGIs and recruits the polycomb repressive complex 1 (PRC1). This contributes to histone H2A lysine 119 ubiquitylation (H2AK119ub1) and gene repression. Unexpectedly, we also find that CGIs are occupied by low levels of PRC1 throughout the genome, suggesting that the KDM2B-PRC1 complex may sample CGI-associated genes for susceptibility to polycomb-mediated silencing. These observations demonstrate an unexpected and direct link between recognition of CGIs by KDM2B and targeting of the polycomb repressive system. This provides the basis for a new model describing the functionality of CGIs as mammalian PREs.DOI: http://dx.doi.org/10.7554/eLife.00205.001

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Section: Resultssupporting

confidence: 92%

KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands

Farcas

Blackledge

Sudbery

et al. 2012

eLife

423

507

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“…The changes observed in the expression of Aass, Nqo1, Prdx4, and Serpinb1b were sufficient to induce the oxidative-stress phenotype of Ndy1 overexpression. The data in this report showing that Ndy1 functions as an activator of transcription are in agreement with recently published data showing that Ndy1 promotes the transcriptional activation of the Hoxd1 gene (47). Other studies, however, have shown that Ndy1 functions as a transcriptional repressor (8,10,39).…”

Section: Discussionsupporting

confidence: 93%

The JmjC Domain Histone Demethylase Ndy1 Regulates Redox Homeostasis and Protects Cells from Oxidative Stress

Polytarchou

Pfau

Hatziapostolou

et al. 2008

Molecular and Cellular Biology

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The histone H3 demethylase Ndy1/KDM2B protects cells from replicative senescence. Changes in the metabolism of reactive oxygen species (ROS) are important for establishing senescence, suggesting that Ndy1 may play a role in redox regulation. Here we show that Ndy1 protects from H 2 O 2 -induced apoptosis and G 2 /M arrest and inhibits ROS-mediated signaling and DNA damage, while knockdown of Ndy1 has the opposite effects. Consistent with these observations, whereas Ndy1 overexpression promotes H 2 O 2 detoxification, Ndy1 knockdown inhibits it. Ndy1 promotes the expression of genes encoding the antioxidant enzymes aminoadipic semialdehyde synthase (Aass), NAD(P)H quinone oxidoreductase-1 (Nqo1), peroxiredoxin-4 (Prdx4), and serine peptidase inhibitor b1b (Serpinb1b) and represses the expression of interleukin-19. At least two of these genes (Nqo1 and Prdx4) are regulated directly by Ndy1, which binds to specific sites within their promoters and demethylates promoter-associated histone H3 dimethylated at K36 and histone H3 trimethylated at K4. Simultaneous knockdown of Aass, Nqo1, Prdx4, and Serpinb1b in Ndy1-expressing cells to levels equivalent to those detected in control cells was sufficient to suppress the Ndy1 redox phenotype.Replicative senescence results primarily from the activation of the DNA damage response, which can be induced by telomere shortening, the aberrant firing of replication origins, activated oncogenes, or oxidative stress. Molecules that inhibit senescence, therefore, may either protect from DNA damage or interfere with the activation of the DNA damage response (3). Earlier studies from this laboratory identified the histone H3 demethylase Ndy1 (Not dead yet-1) as a physiological inhibitor of replicative senescence. Thus, overexpression of Ndy1 promotes immortalization, and knockdown of Ndy1 promotes senescence, of mouse embryo fibroblasts (MEFs) in culture (29). Given that replicative senescence may be a feature of the response to DNA damage, these findings raised the question of whether Ndy1 protects from DNA damage by regulating redox homeostasis and/or the cellular response to oxidative stress.Oxidation and reduction are coupled processes, which in biological systems are aided by enzymes collectively known as oxidoreductases (22). The coupled process of oxidation/reduction frequently gives rise to charged reactive radicals, known collectively as reactive oxygen species (ROS). ROS is an inclusive term for oxygen anions and radicals such as superoxide ( ⅐ O 2Ϫ ) and hydroxyl radicals (OH ⅐ ), hydrogen peroxide (H 2 O 2 ), nitric oxide (NO ⅐ ), and various peroxides (ROOR ⅐ ) (23, 45). ROS are produced in living cells by a variety of mechanisms: electrons escaping from the respiratory chain in mitochondria target oxygen to form ⅐ O 2Ϫ (26), while NADPH oxidase and related enzymes produce ⅐ O 2Ϫ upon activation, and nitric oxide synthase produces NO ⅐ , ⅐ O 2Ϫ , and H 2 O 2 (30, 37). Besides the endogenous sources of ROS, there are also exogenous sources, such as environmental pollutants,...

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“…F-box proteins function as components of SCF-type E3 ubiquitin ligase complexes and may participate in co-repressor complexes (Gearhart et al 2006). The presence of a histone demethylase activity in FBXL10 was shown to be important for regulation of cell senescence and transcription of rRNAs (Jin et al 2004, Takeuchi et al 2006, Frescas et al 2007, He et al 2008, Pfau et al 2008, Yamagishi et al 2008. In our experiments, truncated versions of FBXL10 gene were recovered lacking the 5 0 -terminal part encoding the demethylase domain.…”

Section: Discussionmentioning

confidence: 76%

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Agthoven¹,

Sieuwerts²,

Meijer³

et al. 2010

Endocrine-Related Cancer

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Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct antiestrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.

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Secondary DNA structure formation for Hoxb9 promoter and identification of its specific binding protein

Cited by 11 publications

References 29 publications

KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands

KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands

The JmjC Domain Histone Demethylase Ndy1 Regulates Redox Homeostasis and Protects Cells from Oxidative Stress

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

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