SATB1 (special AT-rich sequence-binding protein-1) is a protein which in humans is encoded by the SATB1 gene.[5] It is a dimeric/tetrameric transcription factor[6] with multiple DNA binding domains (CUT1, CUT2 and a Homeobox domain). SATB1 specifically binds to AT-rich DNA sequences with high unwinding propensity[7] called base unpairing regions (BURs), containing matrix attachment regions (MARs).[8][9][10][11]

SATB1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSATB1, SATB homeobox 1, DEFDA, KTZSL
External IDsOMIM: 602075; MGI: 105084; HomoloGene: 2232; GeneCards: SATB1; OMA:SATB1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 3: 18.35 – 18.45 MbChr 17: 52.04 – 52.14 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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SATB1 is as a key factor for regulating spatial genome organization and subsequently integrating higher-order chromatin architecture with gene regulation.[12] By binding to MARs and tethering these to the nuclear matrix, SATB1 creates chromatin loops.[13][14][15] By changing the chromatin-loop architecture SATB1 is able to change gene transcription.[16] The majority of SATB1 binding sites in the DNA are occupied by CTCF as well,[17] another important chromatin organizer.

Immune system

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SATB1 has a multitude of roles in the development of T cells.

SATB1 plays a role in controlling expression of lineage-specific factors during T cell development, including ThPOK, Runx3, CD4, CD8, and Treg factor Foxp3. SATB1-deficient thymocytes enter inappropriate T lineages and fail to generate the NKT and Treg subsets.[18] The Treg deficiency subsequently causes an auto-immune phenotype in Satb1-deficient mouse models.[19] The auto-immune phenotype is associated with loss of SATB1-dependent spatial rearrangement of the TCRα enhancer and the TCR locus, controlling TCR recombination[20] via downregulation of the Rag1 and Rag2 genes.[21]

Moreover, SATB1 represses IL-2Ralpha and IL-2 expression by recruitment of HDAC1 as part of the NuRD chromatin remodeling complex to a SATB1-bound site in the IL-2Ralpha and IL-2 locus,[22][23] regulating T cell cytokine expression.

Other tissues

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SATB1 has been described to play a role in a variety of different cellular processes, including epidermal differentiation,[24] brain development,[25] X-chromosome inactivation,[26] and embryonic stem cell differentiation.[27]

Structure

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SATB1 contains a ULD, CUTL, CUT1-CUT2 tandem and homeobox domain.

The ULD and CUTL domains at the N-terminal are important for tetramerization and subsequent DNA-binding of SATB1.[28] This N-terminal region can be cleaved off by caspase-6[29][30] and caspase-3[31] during apoptosis, resulting in dissociation from the chromatin.

The CUT1 domain contains a five-helix structure that is crucial for SATB1 binding to MARs with the third helix deeply entering the major groove of the DNA and making direct contacts with the bases.[10] While CUT1 is essential for binding to MAR-sites, the CUT2 domain is dispensable.[9]

The SATB1 homeobox domain confers poor DNA-binding ability by itself, but has been found to increase the DNA-binding affinity and specificity of SATB1 in combination with the CUT domains.[11][9]

Clinical significance

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Rare neurodevelopmental disorders

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Rare high-penetrant heterozygous variants in SATB1 have been identified in neurodevelopmental disorder.[32]

Missense mutations in one of the DNA-binding domains (CUT1 and CUT2) cause a neurodevelopmental syndrome characterized by global developmental delay, moderate to severe intellectual disability, dysmorphic features, teeth abnormalities and early-onset epilepsy (den Hoed-de Boer-Voisin syndrome; DHDBV).[33]

Nonsense and frameshift mutations are associated with a distinct neurodevelopmental condition characterized by mild global developmental delay with variably impaired intellectual development (DEvelopmental delay with dysmorphic Facies and Dental Anomalies; DEFDA).[34]

Cancer

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Higher expression levels of SATB1 have been described to promote tumor growth in breast cancer,[35] glioma,[36] prostate cancer,[37] liver cancer[38] and ovarian cancer,[39] and SATB1 levels have prognostic significance in some of these forms of cancer. Indeed, lowering SATB1 levels have been shown to inhibit proliferation of osteocarcoma[40] and lung adenocarcinoma cells.[41]

In contrast, in CD8+ and CD4 + T cells, Satb1 has been demonstrated to be crucial for anti-tumor immunity by regulating PD-1 expression.[42] T-cells that do not express Satb1 were shown to have less anti-tumor activity,[42] and mice lacking Satb1 expression in CD4+ T cells develop intra-tumoral tertiary lymphoid structures.[43]

Interactions

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SATB1 has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000182568Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023927Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: SATB1 SATB homeobox 1".
  6. ^ Nakagomi K, Kohwi Y, Dickinson LA, Kohwi-Shigematsu T (March 1994). "A novel DNA-binding motif in the nuclear matrix attachment DNA-binding protein SATB1". Molecular and Cellular Biology. 14 (3): 1852–1860. doi:10.1128/MCB.14.3.1852. PMC 358543. PMID 8114718.
  7. ^ Bode J, Kohwi Y, Dickinson L, Joh T, Klehr D, Mielke C, Kohwi-Shigematsu T (January 1992). "Biological significance of unwinding capability of nuclear matrix-associating DNAs". Science. 255 (5041): 195–197. Bibcode:1992Sci...255..195B. doi:10.1126/science.1553545. PMID 1553545.
  8. ^ Dickinson LA, Joh T, Kohwi Y, Kohwi-Shigematsu T (August 1992). "A tissue-specific MAR/SAR DNA-binding protein with unusual binding site recognition". Cell. 70 (4): 631–645. doi:10.1016/0092-8674(92)90432-c. PMID 1505028. S2CID 41115832.
  9. ^ a b c Dickinson LA, Dickinson CD, Kohwi-Shigematsu T (April 1997). "An atypical homeodomain in SATB1 promotes specific recognition of the key structural element in a matrix attachment region". The Journal of Biological Chemistry. 272 (17): 11463–11470. doi:10.1074/jbc.272.17.11463. PMID 9111059.
  10. ^ a b Yamasaki K, Akiba T, Yamasaki T, Harata K (2007-07-25). "Structural basis for recognition of the matrix attachment region of DNA by transcription factor SATB1". Nucleic Acids Research. 35 (15): 5073–5084. doi:10.1093/nar/gkm504. PMC 1976457. PMID 17652321.
  11. ^ a b Ghosh RP, Shi Q, Yang L, Reddick MP, Nikitina T, Zhurkin VB, et al. (July 2019). "Satb1 integrates DNA binding site geometry and torsional stress to differentially target nucleosome-dense regions". Nature Communications. 10 (1): 3221. Bibcode:2019NatCo..10.3221G. doi:10.1038/s41467-019-11118-8. PMC 6642133. PMID 31324780.
  12. ^ Pavan Kumar P, Purbey PK, Sinha CK, Notani D, Limaye A, Jayani RS, Galande S (April 2006). "Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo". Molecular Cell. 22 (2): 231–243. doi:10.1016/j.molcel.2006.03.010. PMID 16630892.
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  16. ^ Kumar PP, Bischof O, Purbey PK, Notani D, Urlaub H, Dejean A, Galande S (January 2007). "Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus". Nature Cell Biology. 9 (1): 45–56. doi:10.1038/ncb1516. hdl:11858/00-001M-0000-0012-E256-8. PMID 17173041. S2CID 23337965.
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  22. ^ Yasui D, Miyano M, Cai S, Varga-Weisz P, Kohwi-Shigematsu T (October 2002). "SATB1 targets chromatin remodelling to regulate genes over long distances". Nature. 419 (6907): 641–645. Bibcode:2002Natur.419..641Y. doi:10.1038/nature01084. PMID 12374985. S2CID 25822700.
  23. ^ Kumar PP, Purbey PK, Ravi DS, Mitra D, Galande S (March 2005). "Displacement of SATB1-bound histone deacetylase 1 corepressor by the human immunodeficiency virus type 1 transactivator induces expression of interleukin-2 and its receptor in T cells". Molecular and Cellular Biology. 25 (5): 1620–1633. doi:10.1128/MCB.25.5.1620-1633.2005. PMC 549366. PMID 15713622.
  24. ^ Fessing MY, Mardaryev AN, Gdula MR, Sharov AA, Sharova TY, Rapisarda V, et al. (September 2011). "p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis". The Journal of Cell Biology. 194 (6): 825–839. doi:10.1083/jcb.201101148. PMC 3207288. PMID 21930775.
  25. ^ Balamotis MA, Tamberg N, Woo YJ, Li J, Davy B, Kohwi-Shigematsu T, Kohwi Y (January 2012). "Satb1 ablation alters temporal expression of immediate early genes and reduces dendritic spine density during postnatal brain development". Molecular and Cellular Biology. 32 (2): 333–347. doi:10.1128/MCB.05917-11. PMC 3255767. PMID 22064485.
  26. ^ Agrelo R, Souabni A, Novatchkova M, Haslinger C, Leeb M, Komnenovic V, et al. (April 2009). "SATB1 defines the developmental context for gene silencing by Xist in lymphoma and embryonic cells". Developmental Cell. 16 (4): 507–516. doi:10.1016/j.devcel.2009.03.006. PMC 3997300. PMID 19386260.
  27. ^ Savarese F, Dávila A, Nechanitzky R, De La Rosa-Velazquez I, Pereira CF, Engelke R, et al. (November 2009). "Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression". Genes & Development. 23 (22): 2625–2638. doi:10.1101/gad.1815709. PMC 2779756. PMID 19933152.
  28. ^ Wang Z, Yang X, Chu X, Zhang J, Zhou H, Shen Y, Long J (May 2012). "The structural basis for the oligomerization of the N-terminal domain of SATB1". Nucleic Acids Research. 40 (9): 4193–4202. doi:10.1093/nar/gkr1284. PMC 3351170. PMID 22241778.
  29. ^ Galande S, Dickinson LA, Mian IS, Sikorska M, Kohwi-Shigematsu T (August 2001). "SATB1 cleavage by caspase 6 disrupts PDZ domain-mediated dimerization, causing detachment from chromatin early in T-cell apoptosis". Molecular and Cellular Biology. 21 (16): 5591–5604. doi:10.1128/MCB.21.16.5591-5604.2001. PMC 87280. PMID 11463840.
  30. ^ Gotzmann J, Meissner M, Gerner C (May 2000). "The fate of the nuclear matrix-associated-region-binding protein SATB1 during apoptosis". Cell Death and Differentiation. 7 (5): 425–438. doi:10.1038/sj.cdd.4400668. PMID 10800076. S2CID 21633620.
  31. ^ Sun Y, Wang T, Su Y, Yin Y, Xu S, Ma C, Han X (March 2006). "The behavior of SATB1, a MAR-binding protein, in response to apoptosis stimulation". Cell Biology International. 30 (3): 244–247. doi:10.1016/j.cellbi.2005.10.025. PMID 16377216. S2CID 26706596.
  32. ^ den Hoed J, de Boer E, Voisin N, Dingemans AJ, Guex N, Wiel L, et al. (February 2021). "Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction". American Journal of Human Genetics. 108 (2): 346–356. doi:10.1016/j.ajhg.2021.01.007. hdl:21.11116/0000-0007-623A-A. PMC 7895900. PMID 33513338.
  33. ^ "Den Hoed-De Boer-Voisin Syndrome; DHDBV". Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University. Entry - #619229. Retrieved 2023-07-08.
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  36. ^ Chu SH, Ma YB, Feng DF, Zhang H, Zhu ZA, Li ZQ, Jiang PC (July 2012). "Upregulation of SATB1 is associated with the development and progression of glioma". Journal of Translational Medicine. 10: 149. doi:10.1186/1479-5876-10-149. PMC 3492129. PMID 22839214.
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  44. ^ a b c d e Yasui D, Miyano M, Cai S, Varga-Weisz P, Kohwi-Shigematsu T (October 2002). "SATB1 targets chromatin remodelling to regulate genes over long distances". Nature. 419 (6907): 641–645. Bibcode:2002Natur.419..641Y. doi:10.1038/nature01084. PMID 12374985. S2CID 25822700.
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Further reading

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