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: