SATB1

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
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

Function

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

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

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

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

Rare neurodevelopmental disorders

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

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

SATB1 has been shown to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000182568 - Ensembl, May 2017
  2. 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. 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. 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.
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Further reading
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