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]}

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

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

References