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April 15th, 2025
Version: 4
University of California San Francisco
genomics
biorxiv

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

Kohwi, Y.Open in Google Scholar•Wong, X.Open in Google Scholar•Grange, M.Open in Google Scholar•Sexton, T.Open in Google Scholar•Richards, H. W.Open in Google Scholar•Kitagawa, Y.Open in Google Scholar•Sakaguchi, S.Open in Google Scholar•Liang, Y.-C.Open in Google Scholar•Chuong, C.-M.Open in Google Scholar•Botchkarev, V.Open in Google Scholaret al.

Mammalian genomes are organized by multi-level folding, yet how this organization contributes to cell type-specific transcription remain unclear. A nuclear protein SATB1 forms a SATB1-rich subnuclear structure that resists high-salt extraction. SATB1 binds in the minor groove of double-stranded base-unpairing regions (BURs), genomic elements with high unwinding propensities. We uncovered that SATB1 establishes a two-tiered chromatin organization, one through indirect binding and another by direct binding of BURs. Published ChIP-seq datasets show SATB1 binding to highly 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 lamina associated domains (LADs), but some (~10%) are found in gene-rich accessible chromatin outside LADs as well. Only a subset of 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.

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