Faculty, Staff and Student Publications

Publication Date

4-22-2025

Journal

Cell Reports

DOI

10.1016/j.celrep.2025.115476

PMID

40158221

Abstract

The clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in the eukaryotic genome. However, the contribution of binding sites within the homotypic clusters of TFBSs (HCTs) to TF binding and target gene expression remains to be understood. Here, we characterize the CHD4 enhancers that harbor unique functional ZNF410 HCTs genome wide. We uncover that ZNF410 controls chromatin accessibility and activity of the CHD4 enhancer regions. We demonstrate that ZNF410 binds to the HCTs in a collaborative fashion, further conferring transcriptional activation. In particular, three ZNF410 motifs (sub-HCTs) located at 3' end of the distal enhancer act as "switch motifs" to control chromatin accessibility and enhancer activity. Mechanistically, the SWI/SNF complex is selectively required to mediate cooperative ZNF410 binding for CHD4 expression. Together, our findings expose a complex functional hierarchy of homotypic clustered motifs, which cooperate to fine-tune target gene expression.

Keywords

Enhancer Elements, Genetic, Humans, Transcription Factors, Chromatin, Protein Binding, Binding Sites, Chromosomal Proteins, Non-Histone, Mi-2 Nucleosome Remodeling and Deacetylase Complex, DNA-Binding Proteins, CP: Molecular biology, SWI/SNF complex, ZNF410, chromatin accessibility, enhancer activity, homotypic clustered motifs, motif cooperation, transcription factor

Published Open-Access

yes

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