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 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.
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.
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]
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]
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]
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]
SATB1 has been shown to interact with:
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