Abstract
Chromatin interactions connect distal regulatory elements to target gene promoters guiding stimulus- and lineage-specific transcription. Few factors securing chromatin interactions have so far been identified. Here, by integrating chromatin interaction maps with the large collection of transcription factor-binding profiles provided by the ENCODE project, we demonstrate that the zinc-finger protein ZNF143 preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements. It binds directly to promoters and associates with lineage-specific chromatin interactions and gene expression. Silencing ZNF143 or modulating its DNA-binding affinity using single-nucleotide polymorphisms (SNPs) as a surrogate of site-directed mutagenesis reveals the sequence dependency of chromatin interactions at gene promoters. We also find that chromatin interactions alone do not regulate gene expression. Together, our results identify ZNF143 as a novel chromatin-looping factor that contributes to the architectural foundation of the genome by providing sequence specificity at promoters connected with distal regulatory elements.
Highlights
Cell fate determination relies on lineage-specific transcription programs set by master transcription factors acting on distal regulatory elements, such as enhancers, and proximal gene promoters[1]
To identify the transcription factor(s) involved in securing chromatin interactions between promoters and distal regulatory elements, we first looked for factors that bridge promoter factors with the CCCTC-binding factor (CTCF)-cohesin cluster
We correlated the chromatin immunoprecipitation (ChIP)-seq signal intensities of more than 70 transcription factors profiled by the Encyclopedia of DNA elements (ENCODE)[17] project across all regions of open chromatin in GM12878 or K562 cells
Summary
Cell fate determination relies on lineage-specific transcription programs set by master transcription factors acting on distal regulatory elements, such as enhancers, and proximal gene promoters[1]. CTCF is known to directly regulate the formation of chromatin interactions in partnership with the cohesin and/or mediator complexes[9] It occupies distal regulatory elements located close to enhancers[5,10,11] and defines the boundaries of topological domains when paired with the cohesin complex[10,12]. The mediator and cohesin complexes lack DNA-binding domains, their recruitment to the chromatin commonly coincides with CTCF13,14 or other transcription factors such as the oestrogen receptor alpha[15]. CTCF and oestrogen receptor alpha bind chromatin far from promoter regions[15,16] and cohesin-binding sites found at promoters relate to tissue-specific transcription[15] This suggests the existence of a yet-to-be identified promoter-bound DNA recognition factor(s) capable of specifying the target gene promoter(s) of distal regulatory elements. Our results demonstrate that ZNF143 is a new factor controlling the formation of chromatin interactions
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