Genome organization by SATB1 binding to base-unpairing regions (BURs) provides a scaffold for SATB1-regulated gene expression.

Fiche publication

Date publication

octobre 2025

Journal

eLife

Auteurs

Membres identifiés du Cancéropôle Est :
Dr SEXTON Thomas

Tous les auteurs :
Kohwi Y, Wong X, Grange M, Sexton T, Richards HW, Kitagawa Y, Sakaguchi S, Liang YC, Chuong CM, Botchkarev VA, Taniuchi I, Reddy KL, Kohwi-Shigematsu T

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/41036778

Résumé

Mammalian genomes are organized by multi-level folding; yet how this organization contributes to cell-type-specific transcription remains unclear. SATB1 forms a nuclear substructure that resists high-salt extraction. SATB1 binds base-unpairing regions (BURs), genomic elements with high unwinding propensities. In mouse thymocytes, we found that SATB1 establishes a two-tiered chromatin organization: one through indirect binding to transcriptionally active DNase 1-accessible chromatin and another by direct binding to BURs in the DNase 1-inaccessible nuclear substructure. Recently published ChIP-seq datasets show SATB1 binding to accessible chromatin at enhancers and CTCF sites, but not to BURs. By employing urea ChIP-seq, which retains only directly bound protein:DNA complexes, we found that BURs, but not CTCF sites, are direct SATB1 binding targets genome-wide. BURs bound to the SATB1 nuclear substructure interact with accessible chromatin, crossing multiple topologically associated domains (TADs). SATB1 is required for these megabase-scale interactions linked to cell-type-specific gene expression. BURs are highly enriched within transcriptionally repressive lamina-associated domains (LADs). Besides these BURs, SATB1 anchors some BURs (18%) outside LADs near genes in otherwise accessible chromatin to the SATB1 nuclear substructure. Only a subset of total BURs is bound to SATB1, depending on cell type. Notably, despite the mutually exclusive SATB1-binding profiles uncovered by the two ChIP-seq methods, we found most peaks in both profiles are valid and require SATB1. Based on these and previous data, we propose that the SATB1 protein network forms a chromatin scaffold, providing an interface that connects accessible chromatin to a subnuclear architectural structure, thereby facilitating the three-dimensional organization linked to cell-type-specific gene expression.