Active and Repressive Chromatin Are Interspersed without Spreading in an Imprinted Gene Cluster in the Mammalian Genome

Regha, Kakkad; Sloane, Mathew A.; Huang, Ru; Pauler, Florian M.; Warczok, Katarzyna E.; Melikant, Balázs; Radolf, Martin; Martens, Joost H.A.; Schotta, Gunnar; Jenuwein, Thomas; Barlow, Denise P.

doi:10.1016/j.molcel.2007.06.024

Cited by 140 publications

(163 citation statements)

References 33 publications

Supporting

Mentioning

142

Contrasting

Order By: Relevance

“…The focal heterochromatin may be able to recruit transcriptional repressor complexes, such as CoREST and H3K4me3 demethylase, to regulate nucleosome occupancy in the active gene loci to repress expression of the cell growth genes. 37,38 This assertion was mainly supported by earlier studies showing that Rb-mediated repression of E2F target genes, including cyclin E, cyclin A2, cyclin D1 and B-Myb, was dependent on the formation of focal heterochromatin induced by SUV39 h1-mediated H3K9me3 and HP1 association. [39][40][41][42] Thus, any measures that impede H3K9me3 will change the overall nucleosome dynamics and destabilize the genome, leading to de-differentiation of the cells, aberrant gene expression and tumorigenic transformation.…”

Section: Discussionmentioning

confidence: 79%

Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3

Chang

Zhang

et al. 2009

Cell Cycle

View full text Add to dashboard Cite

Lung cancer is the most common cancer worldwide, accounting for 1.3 million cancer deaths annually. Despite extensive studies over the past decade, the detailed mechanism about the initiation and development of the lung cancer is still elusive. In the present report, we showed that overexpression of mdig is a common feature of the non-small cell lung cancer. Gene silencing or overexpression of mdig revealed that mdig is involved in demethylation of tri-methyl lysine 9 on histone H3, leading to an increase in ribosomal RNA expression. The transcriptional regulation of ribosomal RNA gene by mdig is achieved through abrogating tri-methyl lysine 9 on histone H3 and enhancing RNA polymerase I occupancy in the promoter region of the ribosomal RNA gene as demonstrated by chromatin immunoprecipitation. The pronounced expression of mdig in lung cancer tissues but not normal lung tissues, thus, suggests that mdig possesses oncogenic property through antagonizing tri-methyl lysine 9 on histone H3 and promoting ribosomal RNA synthesis.

show abstract

Section: Discussionmentioning

confidence: 79%

Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3

Chang

Zhang

et al. 2009

Cell Cycle

View full text Add to dashboard Cite

show abstract

“…H4K20, the only established Suv4-20h1 substrate, is typically not tri-methylated in transcriptionally active domains, and our preliminary studies did not reveal appreciable levels of H4K20-Me3 at glucocorticoid-inducible loci (data not shown). Recent findings, however, indicate that short heterochromatic regions enriched for H4K20-Me3 can be found within actively transcribed genes (24,28). Alternatively, Suv4-20h1 could modify nonhistone factors.…”

Section: Discussionmentioning

confidence: 99%

GRIP1-associated SET-domain methyltransferase in glucocorticoid receptor target gene expression

Chinenov

Sacta

Cruz

et al. 2008

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

View full text Add to dashboard Cite

Transcriptional regulators such as the glucocorticoid receptor (GR) recruit multiple cofactors to activate or repress transcription. Although most cofactors are intrinsically bifunctional, little is known about the molecular mechanisms dictating the specific polarity of regulation. Furthermore, chromatin modifications thought to be confined to silent loci appear in actively transcribed genes suggesting that similar enzymatic activities may mediate constitutive and transient chromatin states. GRIP1, a GR ligand-dependent coregulator of the p160 family can potentiate or inhibit transcription but the molecular contexts and mechanisms that enable GRIP1 corepressor activity are poorly understood. In a yeast 2-hybrid screen with GRIP1 repression domain (RD)-containing fragment, we repeatedly isolated the C-terminal region of a SET domain-containing protein subsequently identified as histone H4 lysine 20 trimethyltransferase, Suv4-20h1. We cloned a full-length Suv4-20h1 and dissected its interaction with GRIP1 in yeast, in vitro, and in mammalian cells. Strict nuclear localization and high salt concentration required for Suv4-20h1 extraction were consistent with its tight association with chromatin. Overexpression of Suv4-20h1 in human U2OS and A549 cells expressing integrated and endogenous GR, respectively, antagonized liganddependent induction of a subset of GR target genes, whereas Suv4-20h1 siRNA-mediated depletion had a reciprocal effect. Inhibition of GR transactivation required both the GRIP1 interacting region of Suv4-20h1 and its catalytic activity. Thus, Suv4-20h1 known exclusively as a factor involved in constitutive heterochromatin maintenance, actively participates in hormone-dependent transcriptional regulation affecting GR target gene expression in a promoter-and cell type-specific manner.

show abstract

“…However, having used fully differentiated lymphoblast cell lines in these experiments it remains possible that spreading might have occurred earlier and receded by the time of assay. It should be noted that the spreading mechanism was also ruled out in the Igf2r region (19), which showed that the active chromatin is interspersed through modifications localized exclusively on regulatory elements flanking active proteins.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of activation of the paternally expressed genes by the Prader-Willi imprinting center in the Prader-Willi/Angelman syndromes domains

Rabinovitz¹,

Kaufman²,

Ludwig³

et al. 2012

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

View full text Add to dashboard Cite

The Prader-Willi syndrome/Angelman syndrome (PWS/AS) imprinted domain is regulated by a bipartite imprinting control center (IC) composed of a sequence around the SNRPN promoter (PWS-IC) and a 880-bp sequence located 35 kb upstream (AS-IC). The AS-IC imprint is established during gametogenesis and confers repression upon PWS-IC on the maternal allele. Mutation at PWS-IC on the paternal allele leads to gene silencing across the entire PWS/AS domain. This silencing implies that PWS-IC functions on the paternal allele as a bidirectional activator. Here we examine the mechanism by which PWS-IC activates the paternally expressed genes (PEGs) using transgenes that include the PWS-IC sequence in the presence or absence of AS-IC and NDN, an upstream PEG, as an experimental model. We demonstrate that PWS-IC is in fact an activator of NDN. This activation requires an unmethylated PWS-IC in the gametes and during early embryogenesis. PWS-IC is dispensable later in development. Interestingly, a similar activation of a nonimprinted gene (APOA1) was observed, implying that PWS-IC is a universal activator. To decipher the mechanism by which PWS-IC confers activation of remote genes, we performed methylated DNA immunoprecipitation (MeDIP) array analysis on lymphoblast cell lines that revealed dispersed, rather than continued differential methylation. However, chromatin conformation capture (3c) experiments revealed a physical interaction between PWS-IC and the PEGs, suggesting that activation of PEGs may require their proximity to PWS-IC.

show abstract

Active and Repressive Chromatin Are Interspersed without Spreading in an Imprinted Gene Cluster in the Mammalian Genome

Cited by 140 publications

References 33 publications

Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3

Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3

GRIP1-associated SET-domain methyltransferase in glucocorticoid receptor target gene expression

Mechanisms of activation of the paternally expressed genes by the Prader-Willi imprinting center in the Prader-Willi/Angelman syndromes domains

Contact Info

Product

Resources

About