A WIZ/Cohesin/CTCF Complex Anchors DNA Loops to Define Gene Expression and Cell Identity

Abstract

Chromosome structure is a key regulator of gene expression. CTCF and cohesin play critical roles in structuring chromosomes by mediating physical interactions between distant genomic sites. The resulting DNA loops often contain genes and their cis-regulatory elements. Despite the importance of DNA loops in maintaining proper transcriptional regulation and cell identity, there is limited understanding of the molecular mechanisms that regulate their dynamics and function. We report a previously unrecognized role for WIZ (widely interspaced zinc finger-containing protein) in DNA loop architecture and regulation of gene expression. WIZ forms a complex with cohesin and CTCF that occupies enhancers, promoters, insulators, and anchors of DNA loops. Aberrant WIZ function alters cohesin occupancy and increases the number of DNA loop structures in the genome. WIZ is required for proper gene expression and transcriptional insulation. Our results uncover an unexpected role for WIZ in DNA loop architecture, transcriptional control, and maintenance of cell identity.

BET inhibition disrupts transcription but retains enhancer-promoter contact

“…Mediator itself has been suggested to physically interact with cohesin 86 . Additional structural proteins may also be important, for example YY1 24 and WIZ 87 .…”

Functional impact of cancer-associated cohesin variants on gene expression and cellular identity

“…Murine embryonic stem cells (V6.5, male, derived from a C57BL/6(F) × 129/sv(M) cross) were grown under standard ESC culture conditions ( Arruda et al 2020 ; Justice et al 2020 ). mESC media contained DMEM KO (Thermo Fisher Scientific, 10829-018), 15% fetal bovine serum (VWR, 97068-085), homemade leukemia inducing factor (LIF), 100 U/ml penicillin, 100 µg/ml streptomycin (Thermo Fisher Scientific, 15140-122), 100 µM beta-mercaptoethanol (Thermo Fisher Scientific, 21-985-023), 1× Non-essential amino acids (Thermo Fisher Scientific, 11140-050), and 1× Glutamax (Thermo Fisher Scientific, 35050-061).…”

“…Genome-edited mESC lines were generated as previously described, with modifications ( Arruda et al 2020 ; Justice et al 2020 ). mESCs were transfected with a single-stranded donor oligonucleotide (ssODN) repair template, and plasmids encoding a synthetic guide RNA (sgRNA), Cas9 and a fluorescent gene (eGFP or mCherry) using Lipofectamine 2000 (Thermo Fisher, 11-668-027).…”

Wiring the Brain by Clustered Protocadherin Neural Codes

“…Neuron-restrictive silencer factor ( NRSF ) regulates the neuron-restrictive expression of Pcdhα through binding to HS5-1 and Pcdhα variable exons [ 50 , 81 ]. In addition, Wiz (widely-interspaced zinc finger-containing protein) defines cell identity by functioning as a DNA loop anchor in collaboration with CTCF and cohesin [ 82 ]. Wiz has been shown to regulate Pcdhβ gene expression in mice [ 83 ].…”