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SATB1 targets chromatin remodelling to regulate genes over long distances

Abstract

Eukaryotic chromosomes are organized inside the nucleus in such a way that only a subset of the genome is expressed in any given cell type, but the details of this organization are largely unknown1,2,3. SATB1 (‘special AT-rich sequence binding 1’), a protein found predominantly in thymocytes4, regulates genes by folding chromatin into loop domains, tethering specialized DNA elements to an SATB1 network structure5. Ablation of SATB1 by gene targeting results in temporal and spatial mis-expression of numerous genes and arrested T-cell development, suggesting that SATB1 is a cell-type specific global gene regulator6. Here we show that SATB1 targets chromatin remodelling to the IL-2Rα (‘interleukin-2 receptor α’) gene, which is ectopically transcribed in SATB1 null thymocytes. SATB1 recruits the histone deacetylase contained in the NURD chromatin remodelling complex to a SATB1-bound site in the IL-2Rα locus, and mediates the specific deacetylation of histones in a large domain within the locus. SATB1 also targets ACF1 and ISWI, subunits of CHRAC and ACF nucleosome mobilizing complexes, to this specific site and regulates nucleosome positioning over seven kilobases. SATB1 defines a class of transcriptional regulators that function as a ‘landing platform’ for several chromatin remodelling enzymes and hence regulate large chromatin domains.

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Figure 1: Chromatin remodelling factors co-purify with SATB1 in DNA affinity chromatography.
Figure 2: SATB1 directly interacts with several chromatin remodelling factors.
Figure 3: SATB1 targets HDAC1, ISWI and ACF1 to the IL-2Rα locus in vivo.
Figure 4: Alteration of nucleosomal positioning in the IL-2Rα locus in SATB1 null thymocytes.

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Acknowledgements

We thank the Joint Genome Institute, especially K. Kadner, for sequencing the BAC clone containing the IL-2Rα locus; Y. Zhang for antibodies against Mi-2 and MTA-2; H.-J. Han and S. Galande for DNA constructs; M. Grimaldi and I. Kukimoto for expressing recombinant SNF2H and hACF1; and C. García-Jiménez for affinity purification of antibodies. We also thank C. Goding and M. Kohwi for comments on the manuscript. This work was supported by the National Institutes of Health (T.K-S.), the Marie Curie Cancer Care foundation (P.V-W.) and training grant AG00266 from the National Institute on Aging (D.Y.).

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Correspondence to Terumi Kohwi-Shigematsu.

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Yasui, D., Miyano, M., Cai, S. et al. SATB1 targets chromatin remodelling to regulate genes over long distances. Nature 419, 641–645 (2002). https://doi.org/10.1038/nature01084

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