Abstract
Eukaryotic chromosomes are packaged in nuclei by many orders of folding.
Little is known about how higher-order chromatin packaging might
affect gene expression. SATB1 is a cell-type specific nuclear protein
that recruits chromatin-remodeling factors and regulates numerous
genes during thymocyte differentiation. Here we show that in thymocyte
nuclei, SATB1 has a cage-like 'network' distribution circumscribing
heterochromatin and selectively tethers specialized DNA sequences
onto its network. This was shown by fluorescence in situ hybridization
on wild-type and Satb1-null thymocytes using in vivo SATB1-bound
sequences as probes. Many gene loci, including that of Myc and a
brain-specific gene, are anchored by the SATB1 network at specific
genomic sites, and this phenomenon is precisely correlated with proper
regulation of distant genes. Histone-modification analyses across
a gene-enriched genomic region of 70 kb showed that acetylation of
histone H3 at Lys9 and Lys14 peaks at the SATB1-binding site and
extends over a region of roughly 10 kb covering genes regulated by
SATB1. By contrast, in Satb1-null thymocytes, this site is marked
by methylation at H3 Lys9. We propose SATB1 as a new type of gene
regulator with a novel nuclear architecture, providing sites for
tissue-specific organization of DNA sequences and regulating region-specific
histone modification.
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