TGF-β-Dependent Active Demethylation and Expression of the p15ink4b Tumor Suppressor Are Impaired by the ZNF217/CoREST Complex

Thillainadesan, Gobi; Chitilian, Jennifer M.; Isovic, Majdina; Ablack, Jailal Nicholas George; Mymryk, Joe S.; Tini, Marc; Torchia, Joseph

doi:10.1016/j.molcel.2012.03.027

Cited by 101 publications

(104 citation statements)

References 47 publications

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“…Furthermore, treatment with 5-Aza-dC or complementation with mouse AID antagonized the effect of AID knockdown on methylation levels in these key promoters. Although this does not prove that methylation levels in these CpG islands are directly modulated by AID, it is consistent with the evidence that AID demethylates promoters of genes that subsequently become transcriptionally active (8,67). Recent studies have described AID's association with RNA polII at gene promoters (68) and with the elongation complex (69), which would suggest that it may regulate gene expression independently of its function in DNA deamination.…”

Section: Knockdown Of Aid Increases Methylation In Promoter Cpg Islanmentioning

confidence: 53%

Activation-induced cytidine deaminase (AID) is necessary for the epithelial–mesenchymal transition in mammary epithelial cells

Muñoz¹,

Lee²,

Takayama³

et al. 2013

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

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Activation-induced cytidine deaminase (AID), which functions in antibody diversification, is also expressed in a variety of germ and somatic cells. Evidence that AID promotes DNA demethylation in epigenetic reprogramming phenomena, and that it is induced by inflammatory signals, led us to investigate its role in the epithelialmesenchymal transition (EMT), a critical process in normal morphogenesis and tumor metastasis. We find that expression of AID is induced by inflammatory signals that induce the EMT in nontransformed mammary epithelial cells and in ZR75.1 breast cancer cells. shRNA-mediated knockdown of AID blocks induction of the EMT and prevents cells from acquiring invasive properties. Knockdown of AID suppresses expression of several key EMT transcriptional regulators and is associated with increased methylation of CpG islands proximal to the promoters of these genes; furthermore, the DNA demethylating agent 5 aza-2'deoxycytidine (5-AzadC) antagonizes the effects of AID knockdown on the expression of EMT factors. We conclude that AID is necessary for the EMT in this breast cancer cell model and in nontransformed mammary epithelial cells. Our results suggest that AID may act near the apex of a hierarchy of regulatory steps that drive the EMT, and are consistent with this effect being mediated by cytosine demethylation. This evidence links our findings to other reports of a role for AID in epigenetic reprogramming and control of gene expression.A ctivation-induced cytidine deaminase (AID) belongs to the AID/apolipoprotein B mRNA editing complex catalytic polypeptide (APOBEC) family of cytidine deaminases and is highly expressed in germinal center B lymphocytes, where it is necessary for somatic hypermutation and class switch recombination of the Ig genes (1-3). However, AID is also expressed at much lower levels during B-cell development, where it mediates B-cell tolerance by an as yet undefined mechanism (4, 5). In addition, AID is present at low levels in pluripotent cells such as oocytes, embryonic germ cells, embryonic stem cells (6), and spermatocytes (7), where it may have a function beyond antibody gene diversification (8-10). AID expression is induced by inflammatory paracrine signals such as interleukin-4 (IL-4), tumor necrosis factor alpha (TNFα), and transforming growth factor beta (TGFβ) (11-13), and it has been detected in multiple epithelial tissues in association with chronic inflammatory conditions that promote tumorigenesis (14-18). AID is also expressed in experimentally transformed human mammary epithelial cells (19), and in several cancer cell lines including breast cancer (20, 21). All of this suggests that AID may function in a variety of somatic and germ cell types.AID has been proposed to participate in the demethylation of methylcytosine in DNA (6,(8)(9)(10). Cytosine methylation is a covalent modification of DNA that is present extensively in the vertebrates, predominantly at CpG dinucleotides, where it has a key role in epigenetic mechanisms that suppress transcription initiation...

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Section: Knockdown Of Aid Increases Methylation In Promoter Cpg Islanmentioning

confidence: 53%

Activation-induced cytidine deaminase (AID) is necessary for the epithelial–mesenchymal transition in mammary epithelial cells

Muñoz¹,

Lee²,

Takayama³

et al. 2013

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

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“…Finally, a completely novel mechanism of transcriptional activation was uncovered where TGF-b was found to activate CDKN2B by inducing active demethylation of the promoter DNA (Thillainadesan et al 2012). CDKN2B is repressed and methylated in the absence of signal by a complex comprising the corepressor complex CoREST (Laugesen and Helin 2014), together with the oncoprotein ZNF217 and the DNA methylase DNMT3A.…”

Section: Smad Interactions With Coactivators and Corepressors Lead Tomentioning

confidence: 99%

Transcriptional Control by the SMADs

Hill

2016

Cold Spring Harb Perspect Biol

289

256

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The transforming growth factor-b (TGF-b) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-b family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

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“…ZNF217, a frequently amplified oncogene, is involved in the negative regulation of the p15ink4b tumor suppressor gene. 76 This is accomplished in concert with DNA methyltransferase 3A (DNMT3A), which prevents active DNA demethylation of the locus. This example illustrates that CoR-EST complexes coordinate several enzymatic activities (histone demethylase, histone deacetylase, DNA methyltransferase) to generate stable repressive chromatin structures.…”

Section: The Corest Proteinmentioning

confidence: 99%