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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE235970 | GEO | 2023/08/30

REPOSITORIES: GEO

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Project description:CTCF (CCCTC-binding factor) is a highly conserved 11-zinc finger DNA binding protein with tens of thousands of binding sites genome-wide. CTCF acts as a multifunctional regulator of transcription, having been previously associated with activator, repressor, and insulator activity. These diverse regulatory functions are crucial for preimplantation development and are implicated in the regulation of numerous lineage-specific genes. Despite playing a critical role in developmental gene regulation, the mechanisms that underlie developmental changes in CTCF recruitment and function are poorly understood. Our previous work suggested that differences in CTCFM-bM-^@M-^Ys binding site sequence may affect the regulation of CTCF recruitment, as well as CTCFM-bM-^@M-^Ys regulatory function. To investigate these two possibilities directly during a developmental process, changes in genome-wide CTCF binding and gene expression were characterized during in vitro differentiation of mouse embryonic stem cells. CTCF binding sites were initially separated into three classes (named LowOc, MedOc, and HighOc) based on similarity to the consensus motif. The LowOc class, with lower-similarity to the consensus motif, is more likely to show changes in binding during differentiation. These more dynamically bound sites are enriched for motifs that confer a lower in vitro affinity for CTCF, suggesting a mechanism where sites with low-binding affinity are more amenable to developmental control. Additionally, by comparing changes in CTCF binding with changes in gene expression during differentiation, we show that LowOc and HighOc sites are associated with distinct regulatory functions. In sum, these results suggest that the regulatory control of CTCFM-bM-^@M-^Ys binding and function is dependent in part upon specific motifs within its DNA binding site. Mouse E14 ES cells were differentiated in vitro for 4.5 days using retinoic acid. RNA-Seq was performed from cells collected before and after differentiation.

Project description:CTCF (CCCTC-binding factor) is a highly conserved 11-zinc finger DNA binding protein with tens of thousands of binding sites genome-wide. CTCF acts as a multifunctional regulator of transcription, having been previously associated with activator, repressor, and insulator activity. These diverse regulatory functions are crucial for preimplantation development and are implicated in the regulation of numerous lineage-specific genes. Despite playing a critical role in developmental gene regulation, the mechanisms that underlie developmental changes in CTCF recruitment and function are poorly understood. Our previous work suggested that differences in CTCFM-bM-^@M-^Ys binding site sequence may affect the regulation of CTCF recruitment, as well as CTCFM-bM-^@M-^Ys regulatory function. To investigate these two possibilities directly during a developmental process, changes in genome-wide CTCF binding and gene expression were characterized during in vitro differentiation of mouse embryonic stem cells. CTCF binding sites were initially separated into three classes (named LowOc, MedOc, and HighOc) based on similarity to the consensus motif. The LowOc class, with lower-similarity to the consensus motif, is more likely to show changes in binding during differentiation. These more dynamically bound sites are enriched for motifs that confer a lower in vitro affinity for CTCF, suggesting a mechanism where sites with low-binding affinity are more amenable to developmental control. Additionally, by comparing changes in CTCF binding with changes in gene expression during differentiation, we show that LowOc and HighOc sites are associated with distinct regulatory functions. In sum, these results suggest that the regulatory control of CTCFM-bM-^@M-^Ys binding and function is dependent in part upon specific motifs within its DNA binding site. Mouse E14 ES cells were differentiated in vitro for 4.5 days using retinoic acid. ChIP-seq for CTCF and an IgG control was performed from cells collected before and after differentiation. For undifferentiated cells, data were generated in two biological replicates.

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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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