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SATB1

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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

6304

20230

Ensembl

ENSG00000182568

ENSMUSG00000023927

UniProt

Q01826

Q60611

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

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]

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: ENSG00000182568 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023927 – Ensembl, 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.
  13. ^ Cai S, Han HJ, Kohwi-Shigematsu T (May 2003). "Tissue-specific nuclear architecture and gene expression regulated by SATB1". Nature Genetics. 34 (1): 42–51. doi:10.1038/ng1146. PMID 12692553. S2CID 974648.
  14. ^ Cai S, Lee CC, Kohwi-Shigematsu T (November 2006). "SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes". Nature Genetics. 38 (11): 1278–1288. doi:10.1038/ng1913. PMID 17057718. S2CID 8540592.
  15. ^ Galande S, Purbey PK, Notani D, Kumar PP (October 2007). "The third dimension of gene regulation: organization of dynamic chromatin loopscape by SATB1". Current Opinion in Genetics & Development. Differentiation and gene regulation. 17 (5): 408–414. doi:10.1016/j.gde.2007.08.003. PMID 17913490.
  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.
  17. ^ Wang B, Ji L, Bian Q (March 2023). "SATB1 regulates 3D genome architecture in T cells by constraining chromatin interactions surrounding CTCF-binding sites". Cell Reports. 42 (4): 112323. doi:10.1016/j.celrep.2023.112323. PMID 37000624. S2CID 257856787.
  18. ^ Kakugawa K, Kojo S, Tanaka H, Seo W, Endo TA, Kitagawa Y, et al. (May 2017). "Essential Roles of SATB1 in Specifying T Lymphocyte Subsets". Cell Reports. 19 (6): 1176–1188. doi:10.1016/j.celrep.2017.04.038. PMID 28494867.
  19. ^ Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R, et al. (February 2017). "Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment". Nature Immunology. 18 (2): 173–183. doi:10.1038/ni.3646. PMC 5582804. PMID 27992401.
  20. ^ Zelenka T, Klonizakis A, Tsoukatou D, Papamatheakis DA, Franzenburg S, Tzerpos P, et al. (November 2022). "The 3D enhancer network of the developing T cell genome is shaped by SATB1". Nature Communications. 13 (1): 6954. Bibcode:2022NatCo..13.6954Z. doi:10.1038/s41467-022-34345-y. PMC 9663569. PMID 36376298.
  21. ^ Hao B, Naik AK, Watanabe A, Tanaka H, Chen L, Richards HW, et al. (May 2015). "An anti-silencer- and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development". The Journal of Experimental Medicine. 212 (5): 809–824. doi:10.1084/jem.20142207. PMC 4419350. PMID 25847946.
  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.
  34. ^ "Developmental Delay With Dysmorphic Facies and Dental Anomalies; DEFDA". Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University. Entry - #619228. Retrieved 2023-07-08.
  35. ^ Han HJ, Russo J, Kohwi Y, Kohwi-Shigematsu T (March 2008). "SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis". Nature. 452 (7184): 187–193. Bibcode:2008Natur.452..187H. doi:10.1038/nature06781. PMID 18337816. S2CID 4429446.
  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.
  37. ^ Mao L, Yang C, Wang J, Li W, Wen R, Chen J, Zheng J (May 2013). "SATB1 is overexpressed in metastatic prostate cancer and promotes prostate cancer cell growth and invasion". Journal of Translational Medicine. 11: 111. doi:10.1186/1479-5876-11-111. PMC 3651708. PMID 23642278.
  38. ^ Tu W, Luo M, Wang Z, Yan W, Xia Y, Deng H, et al. (August 2012). "Upregulation of SATB1 promotes tumor growth and metastasis in liver cancer". Liver International. 32 (7): 1064–1078. doi:10.1111/j.1478-3231.2012.02815.x. PMID 22583549. S2CID 23581044.
  39. ^ Nodin B, Hedner C, Uhlén M, Jirström K (September 2012). "Expression of the global regulator SATB1 is an independent factor of poor prognosis in high grade epithelial ovarian cancer". Journal of Ovarian Research. 5 (1): 24. doi:10.1186/1757-2215-5-24. PMC 3472180. PMID 22992394.
  40. ^ Zhang H, Qu S, Li S, Wang Y, Li Y, Wang Y, et al. (June 2013). "Silencing SATB1 inhibits proliferation of human osteosarcoma U2OS cells". Molecular and Cellular Biochemistry. 378 (1–2): 39–45. doi:10.1007/s11010-013-1591-0. PMID 23516037. S2CID 254798923.
  41. ^ Huang B, Zhou H, Wang S, Lang XP, Wang X (November 2016). "Effect of silencing SATB1 on proliferation, invasion and apoptosis of A549 human lung adenocarcinoma cells". Oncology Letters. 12 (5): 3818–3824. doi:10.3892/ol.2016.5179. PMC 5104178. PMID 27895736.
  42. ^ a b Stephen TL, Payne KK, Chaurio RA, Allegrezza MJ, Zhu H, Perez-Sanz J, et al. (January 2017). "SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells". Immunity. 46 (1): 51–64. doi:10.1016/j.immuni.2016.12.015. PMC 5336605. PMID 28099864.
  43. ^ Chaurio RA, Anadon CM, Lee Costich T, Payne KK, Biswas S, Harro CM, et al. (January 2022). "TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures". Immunity. 55 (1): 115–128.e9. doi:10.1016/j.immuni.2021.12.007. PMC 8852221. PMID 35021053.
  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.
  45. ^ Liu J, Barnett A, Neufeld EJ, Dudley JP (July 1999). "Homeoproteins CDP and SATB1 interact: potential for tissue-specific regulation". Molecular and Cellular Biology. 19 (7): 4918–4926. doi:10.1128/mcb.19.7.4918. PMC 84297. PMID 10373541.
  46. ^ Durrin LK, Krontiris TG (June 2002). "The thymocyte-specific MAR binding protein, SATB1, interacts in vitro with a novel variant of DNA-directed RNA polymerase II, subunit 11". Genomics. 79 (6): 809–817. doi:10.1006/geno.2002.6772. PMID 12036295.

Further reading

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