CTCF physically links cohesin to chromatin

Cellular metabolism alters patterns of gene expression through a variety of mechanisms, including alterations in histone modifications and transcription factor activity. Nicotinamide adenine dinucleotide (NAD)-dependent proteins such as poly(ADP ribose) polymerases (PARPs) and sirtuin deacetylases play important roles in this regulation, thus NAD provides a crucial link between metabolism and these cellular signaling processes. Here, we found that lowering NAD levels in mouse primary cortical neurons led to decreased activity-dependent BDNF expression. The altered BDNF transcription occurred independently of Sirt or Parp activities; instead, low NAD levels promoted increased DNA methylation of the activity-dependent BDNF promoter. Increased methylation at this promoter triggered the dissociation of the insulator protein CTCF as well as the accompanying cohesin from the BDNF locus. The loss of these proteins resulted in histone acetylation and methylation changes at this locus consistent with chromatin compaction and gene silencing. Because BDNF is critical for neuronal function, these results suggest that age-or nutrition-associated declines in NAD levels as well as deficits in cohesin function associated with disease modulate BDNF expression and could contribute to cognitive impairment. B rain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. It plays important roles in regulating neurogenesis, synaptic plasticity, and neuronal survival-functions that are vital to learning, memory, and cognition (1, 2). In the CNS, BDNF transcription is regulated by neuronal activity with high expression in the hippocampus and cortex (3, 4). The BDNF gene contains multiple promoters that generate transcripts containing different noncoding exons spliced to a common single coding exon (4). Of the multiple BDNF mRNAs, transcription initiated from BDNF promoter IV is dramatically activated in neurons treated with KCl, which causes membrane depolarization and subsequent influx of calcium (5, 6). In addition to calcium signaling pathways, BDNF transcription is regulated epigenetically by DNA methylation and subsequent chromatin remodeling. Specifically, DNA methylation at promoter IV is involved in silencing BDNF gene expression via transcriptional repressor methyl-CpG-binding protein (MeCP2) (5-7). Abnormal BDNF transcription resulting from aberrant occupancy of methylated DNA binding sites in its promoter has been implicated in the etiology of Rett syndrome (8), and other abnormalities in BDNF are associated with neurodegenerative disorders, including Huntington, Alzheimer, and Parkinson diseases (2), as well as psychiatric disorders such as depression and schizophrenia (1).Age-associated declines in BDNF levels are thought to contribute to impaired cognitive performance in older individuals (9), as are age-related changes in metabolism (10). Nicotinamide adenine dinucleotide (NAD) is a key molecule that links the metabolic state of the cell with gene expression and cell functions. These l...

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“…5 A and B). These results are consistent with previous reports demonstrating that CTCF is required for positioning cohesin on DNA (20,26).…”

Section: Resultssupporting

confidence: 94%

Nicotinamide adenine dinucleotide (NAD)–regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus

Chang¹,

Zhang²,

Heath

et al. 2010

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

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“…Thus, the presence of CTCF is required for cohesin binding to the sites that we studied, consistent with earlier work indicating that CTCF is required to recruit cohesin complex members to shared sites (19)(20)(21). The direct interaction of CTCF with cohesin subunit SCC3 may underlie such recruitment (27).…”

Section: Numerous Sites Of Ctcf Enrichment Reside Among Silent Olfactorysupporting

confidence: 71%

Cell type specificity of chromatin organization mediated by CTCF and cohesin

Hou

Dale

Dean

2010

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

228

214

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CTCF sites are abundant in the genomes of diverse species but their function is enigmatic. We used chromosome conformation capture to determine long-range interactions among CTCF/cohesin sites over 2 Mb on human chromosome 11 encompassing the β-globin locus and flanking olfactory receptor genes. Although CTCF occupies these sites in both erythroid K562 cells and fibroblast 293T cells, the long-range interaction frequencies among the sites are highly cell type specific, revealing a more densely clustered organization in the absence of globin gene activity. Both CTCF and cohesins are required for the cell-type-specific chromatin conformation. Furthermore, loss of the organizational loops in K562 cells through reduction of CTCF with shRNA results in acquisition of repressive histone marks in the globin locus and reduces globin gene expression whereas silent flanking olfactory receptor genes are unaffected. These results support a genome-wide role for CTCF/cohesin sites through loop formation that both influences transcription and contributes to cell-type-specific chromatin organization and function.chromatin loops | insulator | CTCF | globin | transcription E ukaryotic chromatin is dynamically organized to form distinct transcriptionally active or silent domains (1). Chromatin insulators are proposed to play a role in the establishment of such domains within which proper enhancer-gene interactions occur and improper ones are excluded (2). Insulators can function as boundary elements between active and silent chromatin domains and can also interfere with enhancer-gene interaction when placed between them. Evidence also suggests that insulators are involved in higher-order chromatin organization by clustering together with other insulators. Such "insulator bodies" can be visualized at the nuclear periphery of certain cells in Drosophila and are thought to coalesce through the interaction of proteins such as Su(Hw) and Drosophila CTCF (3, 4).In mammalian cells, insulators are bound by CTCF, a protein with 11 zinc fingers through which it can bind to a range of DNA sequences, to itself, and to nuclear structural proteins such as nucleophosmin and matrix attachment regions (MARs) (2). Although insulators would be expected to reside primarily in intergenic regions where they could provide boundary or enhancer blocking activity, genome scans of CTCF enrichment show that CTCF sites are overrepresented in genes and promoter regions, with only 41-56% at intergenic locations (5). In Drosophila, between about 49% and 64% of insulator sites are located in intergenic regions (4). Thus, although CTCF sites are proposed to be insulators, their in vivo functions may not be limited to insulation. Recently, cohesin has been reported to colocalize at most sites of CTCF enrichment and to play a role in transcriptional insulation, but the significance of this joint occupancy to higher-order chromatin structures is unknown (6).In the Igf2/H19 locus, CTCF binding to the imprinting control region on the maternal allele is required to loop ...

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“…The complex forms a ring-like protein structure that is thought to embrace two DNA helices. Surprisingly at the time, cohesin was also found to bind chromatin in post-mitotic cells, with half of its binding sites overlapping with CTCF sites [38][39][40]. Cohesin association to these sites is dependent on the presence of CTCF: without CTCF, cohesin still binds to chromatin but is no longer found at specific sequences.…”

Section: Ctcf and Cohesin Share Dna Binding Sitesmentioning

confidence: 99%

“…In contrast, CTCF does not rely on cohesin for finding its DNA binding sites. One possibility is that bound CTCF serves as a roadblock or barrier to position a sliding cohesin molecule on the chromatin template [38][39][40][41][42].…”

Section: Ctcf and Cohesin Share Dna Binding Sitesmentioning

confidence: 99%

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

Holwerda

Laat

2013

Phil. Trans. R. Soc. B

192

170

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CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.

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CTCF physically links cohesin to chromatin

Cited by 444 publications

References 47 publications

Nicotinamide adenine dinucleotide (NAD)–regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus

Nicotinamide adenine dinucleotide (NAD)–regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus

Cell type specificity of chromatin organization mediated by CTCF and cohesin

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

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