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 ofHDAC1 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:
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.
A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.
In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.
Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.
Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.
GATA3 is a transcription factor that in humans is encoded by the GATA3 gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.
Cux1 is a homeodomain protein that in humans is encoded by the CUX1 gene.
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 is a protein that in humans is encoded by the SMARCA5 gene.
Chromodomain-helicase-DNA-binding protein 3 is an enzyme that in humans is encoded by the CHD3 gene.
Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the CHD4 gene. CHD4 is the core nucleosome-remodelling component of the Nucleosome Remodelling and Deacetylase (NuRD) complex.
Metastasis-associated protein MTA2 is a protein that in humans is encoded by the MTA2 gene.
DNA/RNA-binding protein KIN17 is a protein that in humans is encoded by the KIN gene.
Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.
Bromodomain adjacent to zinc finger domain protein 1A is a protein that in humans is encoded by the BAZ1A gene.
High mobility group nucleosome-binding domain-containing protein 3 is a protein that in humans is encoded by the HMGN3 gene.
Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome. The field is analogous to genomics and proteomics, which are the study of the genome and proteome of a cell. Epigenetic modifications are reversible modifications on a cell's DNA or histones that affect gene expression without altering the DNA sequence. Epigenomic maintenance is a continuous process and plays an important role in stability of eukaryotic genomes by taking part in crucial biological mechanisms like DNA repair. Plant flavones are said to be inhibiting epigenomic marks that cause cancers. Two of the most characterized epigenetic modifications are DNA methylation and histone modification. Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation/development and tumorigenesis. The study of epigenetics on a global level has been made possible only recently through the adaptation of genomic high-throughput assays.
Epigenome editing or epigenome engineering is a type of genetic engineering in which the epigenome is modified at specific sites using engineered molecules targeted to those sites. Whereas gene editing involves changing the actual DNA sequence itself, epigenetic editing involves modifying and presenting DNA sequences to proteins and other DNA binding factors that influence DNA function. By "editing” epigenomic features in this manner, researchers can determine the exact biological role of an epigenetic modification at the site in question.
H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.
Nuclear organization refers to the spatial distribution of chromatin within a cell nucleus. There are many different levels and scales of nuclear organisation. Chromatin is a higher order structure of DNA.
Sanjeev Anant Galande is an Indian cell biologist, epigeneticist, academic, former Chair of Biology and the Dean of Research and Development at the Indian Institute of Science Education and Research, Pune He heads the Laboratory of Chromatin Biology and Epigenetics at Indian Institute of Science Education and Research, Pune. He is the founder of the Centre of Excellence in Epigenetics at IISER Pune and is known for his studies on higher-order chromatin architecture and how it influences spatiotemporal changes in gene expression. He is an elected fellow of the Indian National Science Academy and the Indian Academy of Sciences and a recipient of the National Bioscience Award for Career Development of the Department of Biotechnology. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards, in 2010, for his contributions to biological sciences.
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