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A genome-wide map of CTCF multivalency redefines the CTCF code

ABSTRACT: The “CTCF code” hypothesis posits that CTCF pleotropic functions are driven by recognition of diverse DNA sequences through combinatorial use of its 11 zinc fingers (ZFs). This model however is supported by in vitro binding studies of a limited number of sequences. To directly test CTCF multivalency in vivo we here define ZF binding requirements at ~50,000 genomic sites in primary lymphocytes. We find that CTCF reads sequence diversity through ZF clustering. ZFs4-7 anchor CTCF to ~80% of targets containing the 20bp core motif. Non-conserved flanking sequences are recognized by ZFs1-2 and ZFs8- 11 clusters, which also stabilize CTCF broadly. Alternatively, CTCF employ ZFs9-11 to associate with a second phylogenetically-conserved upstream motif at ~15% of its sites. Individually, ZFs increase overall binding affinity and chromatin residence time. Unexpectedly, we also uncover a conserved downstream DNA motif that destabilizes CTCF occupancy. CTCF thus associates with a wide array of DNA modules via combinatorial clustering of its 11 ZFs.

ORGANISM(S): Mus musculus Mus spretus

PROVIDER: GSE33819 | GEO | 2011/11/19

SECONDARY ACCESSION(S): PRJNA148151

REPOSITORIES: GEO

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Genome-wide mapping of CTCF binding in asynchronous and mitotic cells

Project description:CCCTC-binding factor (CTCF), a conserved and essential regulator of genome architecture bearing a unique complement of 11 zinc fingers (ZFs), has been reported to remain associated with chromatin throughout mitosis and has thus been proposed to act as a bookmark to ensure rapid reestablishment of chromatin structure after cell division. However, little is known about how CTCF is regulated during mitosis. Using a phospho-specific antibody, we found that phosphorylation of CTCF threonine 431, contained within an atypical ZF linker unique to vertebrate CTCF, is highly enriched in mitotic cells and that this phosphorylated form of CTCF is preferentially localized to mitotic chromosomes. We show that T431 mutations abolish the association of CTCF with mitotic chromatin, arguing that T431 phosphorylation is necessary for CTCF mitotic retention. Furthermore, mutation of the CTCF paralog BORIS to accommodate phosphorylation at the residue corresponding to CTCF T431 induces mitotic retention of BORIS. Our data support previous work demonstrating mitotic retention of CTCF and provide new insight into how CTCF remains associated with chromatin during mitosis. Furthermore, our results indicate that phosphorylation of ZF linkers is not exclusively associated with dissociation of ZF-containing proteins from DNA during mitosis.

2019-12-31 | GSE102019 | GEO

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Project description:The multivalent binding of CTCF to a variety of DNA sequences is thought to underlie its ability to mediate a large repertoire of cellular functions. CTCF is a 11 zinc-finger (ZF) protein that is anchored to a majority of its target sites via binding to a 20 base-pair core DNA sequence. Yet the diversity of CTCF binding sites (CBS) has not fully been characterized. Here we assessed CTCF occupancy in cultured mouse cortical neurons as a function of neuronal activity and observed that ~ 22 % of CBS lack the consensus CTCF motif. We report that sequence diversity at most of these atypical CBS is not random but involves degeneracy at specific nucleotide positions within the core CTCF position weight matrix (PWM) that likely affect the binding of ZFs 6 and 7. Surprisingly, degeneracy at the same nucleotides not only define most atypical CBS, but also CBS within most gene promoters, and CBS that are dynamically altered following neuronal stimulation, revealing how atypical CTCF binding could affect gene activity. Dynamic CBS across neural differentiation and neuronal stimulation are found both within and outside loop anchors and TADs, indicating that dynamic CBS could regulate gene activity independently of loop anchoring. Finally, we identified a second mode of atypical CTCF binding that defines most tissue-specific CBS. Unlike other atypical CBS, tissue-specific CBS largely bind sequences unrelated to the core CTCF motif and are enriched within the bodies of tissue-specific genes. Overall, these results indicate how CTCF binding at atypical CBS could allow it to dynamically regulate gene activity patterns during differentiation, development, and in response to environmental cues.

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Atypical modes of CTCF binding facilitate tissue-specific and neuronal activity-dependent gene expression states [CTCF_ChIP-seq]

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Auxin-inducible degron 2 system deciphers functions of CTCF domains in transcriptional regulation [RNA-Seq]

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