Transcriptional repression by the insulator protein CTCF involves histone deacetylases

Lutz, M.; Burke, Les J.; Barreto, Guillermo; Goeman, Frauke; Greb, Heiko; Arnold, Rüdiger; Schultheiß, Holger; Brehm, Alexander; Kouzarides, Tony; Lobanenkov, Victor; Renkawitz, Rainer

doi:10.1093/nar/28.8.1707

Cited by 133 publications

(130 citation statements)

References 52 publications

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“…SIN3A is a transcriptional regulator belonging to the Sin3-histone deacetylase core complex (25,26). Notably, SIN3A protein has conserved motifs that bind to the chromatin insulator protein CCCTC-binding factor (CTCF), a ubiquitously expressed, highly conserved transcriptional repressor that recruits SIN3A and other proteins to the promoters of target genes (27,28). Importantly, the CFTR locus contains functional CTCF-binding sites (29).…”

Section: Resultsmentioning

confidence: 99%

A microRNA network regulates expression and biosynthesis of wild-type and ΔF508 mutant cystic fibrosis transmembrane conductance regulator

Ramachandran

Karp²,

Jiang³

et al. 2012

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

110

126

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Production of functional proteins requires multiple steps, including gene transcription and posttranslational processing. MicroRNAs (miRNAs) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that miRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with an miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl − permeability independent of elevated mRNA levels. An miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, ΔF508, causes protein misfolding, protein degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-ΔF508 and restored Cl − transport to cystic fibrosis airway epithelia. This miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process more broadly than recognized previously. This discovery also provides therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation.

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Section: Resultsmentioning

confidence: 99%

A microRNA network regulates expression and biosynthesis of wild-type and ΔF508 mutant cystic fibrosis transmembrane conductance regulator

Ramachandran

Karp²,

Jiang³

et al. 2012

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

110

126

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“…The mechanism by which CTCF prevents transcription may involve the binding of SIN3A and associated HDACs to an internal 11 Zn fingercontaining region of CTCF and possibly additional corepressors to the C-terminus. 44 There may be additional mechanisms by which DNA methylation affects transcription. In vitro studies have shown that methylation at cytosine residues can cause several changes in DNA structure (reviewed in 45 ).…”

Section: Methylation and Transcriptionmentioning

confidence: 99%

DNA methylation, imprinting and cancer

Plass¹,

Soloway

2002

Eur J Hum Genet

139

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It is well known that a variety of genetic changes influence the development and progression of cancer. These changes may result from inherited or spontaneous mutations that are not corrected by repair mechanisms prior to DNA replication. It is increasingly clear that so called epigenetic effects that do not affect the primary sequence of the genome also play an important role in tumorigenesis. This was supported initially by observations that cancer genomes undergo changes in their methylation state and that control of parental allele-specific methylation and expression of imprinted loci is lost in several cancers. Many loci acquiring aberrant methylation in cancers have since been identified and shown to be silenced by DNA methylation. In many cases, this mechanism of silencing inactivates tumour suppressors as effectively as frank mutation and is one of the cancer-predisposing hits described in Knudson's two hit hypothesis. In contrast to mutations which are essentially irreversible, methylation changes are reversible, raising the possibility of developing therapeutics based on restoring the normal methylation state to cancer-associated genes. Development of such therapeutics will require identifying loci undergoing methylation changes in cancer, understanding how their methylation influences tumorigenesis and identifying the mechanisms regulating the methylation state of the genome. The purpose of this review is to summarise what is known about these issues.

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“…3 Ctcf regulates chromatin architecture together with cohesion proteins, which are enriched at Ctcf-binding sites. [5][6][7] In addition, multiple functions of Ctcf are enabled by interaction with different binding partners like transcription factors (Yy1, Kaiso and YB-1), [8][9][10] chromatin modifying proteins (Sin3a, CHD8, Suz12), [11][12][13] RNA polymerase II 14 and poly(ADP-ribose) polymerase-1. 15 Recently, Ctcf was found to control MHC class II gene expression, 16 and it was reported that enforced overexpression of Ctcf in DC caused increased apoptosis, reduced proliferation and impaired differentiation.…”

Section: Introductionmentioning

confidence: 99%