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ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.

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.

SUBMITTER: Bailey SD

PROVIDER: S-EPMC4431651 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.

Bailey Swneke D SD Zhang Xiaoyang X Desai Kinjal K Aid Malika M Corradin Olivia O Cowper-Sal Lari Richard R Akhtar-Zaidi Batool B Scacheri Peter C PC Haibe-Kains Benjamin B Lupien Mathieu M

Nature communications 20150203

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 r ...[more]

PMID: 25645053

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Project description:BackgroundThe regulation of chromatin accessibility is essential in eukaryotic cells as one of several mechanisms that ensure gene activation occurs at appropriate times and in appropriate cell types. Accordingly, mutations in chromatin remodeling proteins are linked to many different developmental disorders and cancers. One example of a chromatin protein that has been linked to both developmental abnormalities and cancer is BPTF/NURF301, the largest subunit of the Nucleosome Remodeling Factor (NuRF) complex. The BPTF subunit is not only important for the formation of NuRF but also helps direct its activity to particular regions of chromatin by preferentially binding histone H3 lysine four trimethylation (H3K4me3). Notably, defects caused by knockdown of bptf in Xenopus embryos mimic those caused by knockdown of wdr5, a core subunit of all H3K4me3 methyltransferase complexes. However, the mechanistic details of how and where BPTF/NuRF is recruited to regulate gene expression vary between studies and have been largely tested in vitro and/or in cultured cells. Improving our understanding of how this chromatin remodeling complex targets specific gene loci and regulates their expression in an organismal context will provide important insight into how pathogenic mutations disrupt its normal, in vivo, cellular functions.ResultsHere, we report our findings on the role of BPTF in maintaining chromatin accessibility and essential function in planarian (Schmidtea mediterranea) stem cells. We find that depletion of planarian BPTF primarily affects accessibility at gene promoters near transcription start sites (TSSs). BPTF-dependent loss of accessibility did not correlate with decreased gene expression when we considered all affected loci. However, we found that genes marked by Set1-dependent H3K4me3, but not MLL1/2-dependent H3K4me3, showed increased sensitivity to the loss of BPTF-dependent accessibility. In addition, knockdown of bptf (Smed-bptf) produces loss-of-function phenotypes similar to those caused by knockdown of Smed-set1.ConclusionsThe S.mediterranea homolog of NuRF protein BPTF (SMED-BPTF) is essential for normal homeostasis in planarian tissues, potentially through its role in maintaining chromatin accessibility at a specific subset of gene promoters in planarian stem cells. By identifying loci that lose both chromatin accessibility and gene expression after depletion of BPTF, we have identified a cohort of genes that may have important functions in stem cell biology.

Project description:BackgroundGene promoters have guided evolution processes for millions of years. It seems that they were the main engine responsible for the integration of different mutations favorable for the environmental conditions. In cooperation with different transcription factors and other biochemical components, these regulatory regions dictate the synthesis frequency of RNA molecules. Predominantly in the last decade, it has become clear that nuclear organization impacts upon gene regulation. To fully understand the connections between Homo sapiens chromosomes and their gene promoters, we analyzed 1200 promoter sequences using our Kappa Index of Coincidence method.ResultsIn order to measure the structural similarity of gene promoters, we used two-dimensional image-based patterns obtained through Kappa Index of Coincidence (Kappa IC) and (C+G)% values. The center of weight of each promoter pattern indicated a structure similarity between promoters of each chromosome. Furthermore, the proximity of chromosomes seems to be in accordance to the structural similarity of their gene promoters. The arrangement of chromosomes according to Kappa IC values of promoters, shows a striking symmetry between the chromosome length and the structure of promoters located on them. High Kappa IC and (C+G)% values of gene promoters were also directly associated with the most frequent genetic diseases. Taking into consideration these observations, a general hypothesis for the evolutionary dynamics of the genome has been proposed. In this hypothesis, heterochromatin and euchromatin domains exchange DNA sequences according to a difference in the rate of Slipped Strand Mispairing and point mutations.ConclusionsIn this paper we showed that gene promoters appear to be specific to each chromosome. Furthermore, the proximity between chromosomes seems to be in accordance to the structural similarity of their gene promoters. Our findings are based on comprehensive data from Transcriptional Regulatory Element Database and a new computer model whose core is using Kappa index of coincidence.

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ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.

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ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.

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