Genome-wide targeting of the epigenetic regulatory protein CTCF to gene promoters by the transcription factor TFII-I

Abstract

CCCTC-binding factor (CTCF) is a key regulator of nuclear chromatin structure and gene regulation. The impact of CTCF on transcriptional output is highly varied, ranging from repression to transcriptional pausing and transactivation. The multifunctional nature of CTCF may be directed solely through remodeling chromatin architecture. However, another hypothesis is that the multifunctional nature of CTCF is mediated, in part, through differential association with protein partners having unique functions. Consistent with this hypothesis, our mass spectrometry analyses of CTCF interacting partners reveal a previously undefined association with the transcription factor general transcription factor II-I (TFII-I). Biochemical fractionation of CTCF indicates that a distinct CTCF complex incorporating TFII-I is assembled on DNA. Unexpectedly, we found that the interaction between CTCF and TFII-I is essential for directing CTCF to the promoter proximal regulatory regions of target genes across the genome, particularly at genes involved in metabolism. At genes coregulated by CTCF and TFII-I, we find knockdown of TFII-I results in diminished CTCF binding, lack of cyclin-dependent kinase 8 (CDK8) recruitment, and an attenuation of RNA polymerase II phosphorylation at serine 5. Phenotypically, knockdown of TFII-I alters the cellular response to metabolic stress. Our data indicate that TFII-I directs CTCF binding to target genes, and in turn the two proteins cooperate to recruit CDK8 and enhance transcription initiation.

Understanding epigenetic architecture of suicide neurobiology: A critical perspective

“…The identification of additional polymorphic CpG site located in close proximity to other four sites failed to produce a significant association with suicide after genotyping 33 suicide completers. This observation of site-specific differential methylation pattern with a negative effect on corresponding transcript expression was supported by the mapping of CTCF binding site overlapped with four CpG sites, which is in agreement with the observed distribution of 1.42% 3′UTR specific CTCF binding across the whole eukaryotic genome apart from 5.34% promoter specific distribution (Pena-Hernandez et al, 2015). Most likely, the characterization of a CTCF binding site in the same area of preoccupying methylated CpG sites at the 3′UTR transcriptional unit of TRKB.T1 holds a strong possibility towards abated interaction of CTCF within this intragenic region.…”

RNA interactions with CTCF are essential for its proper function

“…Thus far, CTCF binding to DNA seems unaffected by other factors as the knockdown of most of its binding partners is ineffectual. One exception is the general transcription factor II-I (TFII-I) that seems to stabilize CTCF binding at promoter regions (Peña-Hernández et al, 2015). In the context of our observations under TI (Figure 1), the knockdown of TFII-I most likely affects the transcription of its target genes and hence the decrease in CTCF binding might be an indirect effect of disrupting transcription.…”

CTCF: making the right connections

“…For example, Smad proteins are associated with CTCF at the Igf2/H19 imprinted control region (Bergstrom et al 2010) and at many sites in Drosophila (Van Bortle et al 2014). The general transcription factor II-I (TFII-I) helps stabilize CTCF binding at certain promoter-proximal regions (Pena-Hernandez et al 2015). The DEAD-box helicase p68 is associated in HeLa cells with 7% of CTCF sites (Yao et al 2010).…”