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Oct4 (pink)/Sox2 (yellow): binding DNA structure. Method: X-RAY DIFFRACTION (3.451 Å)

Contents

Introduction

Oct4 and Sox2 are two transcription factors (TFs) involved in various roles in murine and primate cells, mainly related to the maintenance of pluripotency and self-renewal properties in embryonic stem cells. These two factors, encoded by the POU5F1 (POU Class 5 Homeobox 1) and SOX2 (SRY-Box Transcription Factor 2) genes, respectively, serve as reprogramming TFs and occupy the same target genes in vivo [1][2], forming the complex OCT4-SOX2, which is the main way in which they act, although they are not obligate heterodimers in solution.

OCT4 and SOX2 Transcription Factors

OCT4

The OCT4 transcription factor (octamer-binding transcription factor 4), also known as OCT-3, OCT3 / 4, OTF3 or NF-A3, was discovered almost three decades ago, where its use relationship with pluripotent CTE in primate and rodent species [3]. This protein is encoded by the POU5F1 gene, which is located on chromosome 6 in humans and 17 in rats, and belongs to the POU family (Pit, October, Unc) of DNA-binding proteins, which regulate the expression of target genes [3][4]. In humans, through alternative splicing, POU5F1 generates less than eight distinct RNA transcripts, these being OCT4A, OCT4B-190, OCT4B-265, OCT4B-164, OCT4B1 and more recently reported as OCT4C, OCT4C1 and OCT4B4 variants [4].

In addition to the generated isoforms, many studies have been carried out mainly with respect to the functions of the OCT4A isoform. Studies targeting the OCT4B isoforms (190, 265 and 164) that are not able to support an automatic restoration of the CTE, but they can respond to cellular stress, whereas the functions of OCT4B1, OCT4C and OCT4C1 have not yet been clarified[5]. OCT4A is normally expressed in the early stages of embryonic development and represents one of the main regulatory factors for pluripotency and self-review of embryonic stem cells, being considered a marker of pluripotency[6]. A further differentiation of CTE into cells used for different tissues depends on rapid and rapid expression of OCT4A, and these cells are differentiated remain with the OCT4A factor silenced [7][8][9]. However, we have already documented an open expression of transcription factors such as OCT4, SOX2 and NANOG, together or controlled, lead to tumors, metastases and the greatest recurrence after use, in different types of cancer [3].

SOX2

The SOX/Sox (SRY homology box) family of proteins comprises 20 individual members in man and mouse [10], which SOX2 is the most explored. SOX proteins are principally defined by a conserved DNA-binding element, the so-called high mobility group (HMG) that relates to a transcriptional master regulator of virility (i.e., SEX determining factor Y, SRY) and thus functionally qualifies SOX/Sox proteins as DNA-binders [11][12]. While Sox proteins contribute to various cellular functionalities, reprogramming capacity is largely confined to members of the SoxB1 group (i.e., Sox1, Sox2, and Sox3)[13]. SOX2 significantly often imposes transcription modulatory in conjunction with co-factors, such as Oct3/4.

Embryonic Expression

OCT4

In humans, the POUF5F1 alternative splicing gives rise to two Oct4 isoforms, Oct4-IA and Oct4-IB, that differs by the N-terminal region. Oct4-IA is required to self-renewal maintenance of stem cells and Oct4-IB is not related to stemness [14] [15]. Oct4 is present in all stages of embryo development [16] [17] [18]. The Oct4 expression pattern differs between the blastomeres in the same development stage by the protein cytoplasmic localization[19]. From the unfertilized oocyte to the solid morula no Oct4 protein is observed in the nucleus [19]. During compaction, Oct4 expression becomes ubiquitous and abundant in the nucleus of all morula blastomeres [19]. In the blastocyst, the Oct4 mRNA and protein are present in the inner cell mass [18].

Maternal murine Oct4 mRNA and protein are deposited in the oocyte and they are necessary for the development until the stage of 4 cells. Proteins are present at low levels at these early stages of murine embryogenesis. Transcription of zygotic Pou5f1 gene is activated at the 4 to 8-cell stage [20] [21] [22] [23]. With the blastocyst is formation, the expression of Oct4 remains high in the inner cell mass and it is not observed in the trophectoderm. After the murine embryo implantation, the transient upregulation of Oct4 in a subset of cells from the inner cell mass, triggers their differentiation into hypoblast (primitive endoderm). After that, the Oct4 expression decreases in these cells [20] [21] [22] [23]. During gastrulation, Oct4 is down-regulated and, after day 8 of gestation, it is confined to primordial germ cells [20] [22] [24] [25].

SOX2

Sox2 is persistently expressed during embryonic development and it is first expressed in the morula stage. Later it becomes specifically located in the inner cell mass of blastocyst and epiblast [26]. After gastrulation it is predominantly expressed in the central nervous system [27]. It is known that zygotic deletion of Sox2 is lethal due to the failure to form pluripotent epiblast whilst the absence of Sox2 has little effect on the trophectoderm formation [26]. The depletion of Sox2 compromised the stemness of both mouse and human embryonic stem cells, changing their morphology and pluripotent marker expression and they differentiate primarily into trophectoderm [28] [29].


The OCT4-SOX2 mechanism in the nucleosome

Nucleosome with OCT4-SOX2 motif at SHL-6. Method: ELECTRON MICROSCOPY (3.49 Å)

OCT4-SOX2-bound nucleosome - SHL+6. Method: ELECTRON MICROSCOPY (3.42 Å)

Transcription factors bind to DNA at specific sequene motifs. Once they're bound, the TFs are capable of regulating gene expression and govern cell identity, making it either harder or easier for RNA polymerase to bind to the promoter of the gene.

The chromatin usually restricts TFs DNA access to over 95% of nucleosomal DNA, due to the nucleosome architecture with histones H2A, H2B, H3, and H4 and its two DNA gyres. The nucleosome is the chromatin basic unit, composed of a 147 pb DNA segment wrapped around 8 histone proteins. It is a convention that the sites in which a DNA major groove is pointed to the nucleosome core are called "superhelix location" (SHL). The SHL are enumerated from 0 to ±7, having 0 as the nucleosome main axis, known as "dyad".

There are two possible scenarios for nucleossomal TF-engagement in this situation: TF binding without changing the nucleosomal architecture, or TF-mediated changes to the nucleosome by distorting the histone core, looping the DNA, or taking advantage of nucleosome unwrapping dynamics at the entry-exit sites[30]. The OCT4-SOX2 binds preferably in the SHL-6 site (Fig.1)[30] and both of them act in the DNA removal from the core histones [31]. OCT4 has a bipartite DNA binding domain (DBD) comprised of a POU-specific (POUS) and POU-homeo-domain (POUHD) separated by 17-residues (Fig.2) and SOX2 has a high-mobility group (HMG) domain (Fig.2) [30] [31] [23]. The OCT4-POUS and SOX2-HMG DBDs engage major and minor grooves, respectively [31]. The DNA remains attached and straightened around the OCT4 site but is detached around the SOX2 motif [31].

OCT4 recognizes a partial motif, engaging DNA with its POUS domain, whereas the POUHD is not engaged [30]. On free DNA, both POU domains engage the major groove over 8bp on opposite sides of the DNA [31]. SOX2 competes with histones for DNA binding and kinks DNA by ~90° at SHL-6.5 away from the histones (Fig.3)[30] [23]. This is accomplished by intercalation of the SOX2 Phe48 and Met49 ‘wedge’ at the TT base step [23]. SOX2 kinks the DNA and synergistically with OCT4 releases the DNA from the core histones (Movie1[30]).


Image:OCT4-SOX2-NCPSHL+6 model(1).jpeg

Figure 1 - OCT4-SOX2-NCPSHL+6 model[30].

Image:Domain schematic of OCT4 and SOX2 constructs.jpeg

Figure 2 - Domain schematic of OCT4 and SOX2 constructs[30].

Image:Comparison of the unbound nucleosome DNA (blue) with the OCT4-SOX2 bound nucleosome structure (grey).jpeg

Figure 3 - OCT4 SOX2 lifts the entry exit DNA away from the histone core. Comparison of the unbound nucleosome DNA (blue) with the OCT4-SOX2 bound nucleosome structure (grey). The DNA is kinked ~90° away from the histones. Residues at the OCT4-DNA interface are shown in sticks. POUS motif nucleotides are shown as ribose and base rings[30].


Gatekeeper for embryonic stem cell pluripotency

The pluripotent identity is ruled by transcriptional factor such as Oct4 and Sox2, that act as key pluripotency regulators among the mammals [3]. Oct4 keeps the undifferentiated cells from becoming trophoblast or endoderm [3] and Sox2 is critical in the formation of pluripotent epiblast cells [32]. The forced expression of Oct4 in Sox2-null mouse embryonic stem cells can rescue the pluripotency, indicating that the role of Sox2 in maintaining the pluripotent state of embryonic stem cells is primarily to sustain a sufficient level of Oct4 expression [28] [29]. Oct4 and Sox2 cooperate to keep the pluripotency of embryonic stem cells by co-occupying a large number of enhancers and/or promoters and regulating the expression levels of their target genes [32]. They activate the transcription of genes involved in the self renewal of embryonic stem cells and besides, they bind themselves to the promoters of their own genes activating them [3].

Yamanaka reprogramming factors and Induced Pluripotend Stem Cells (iPSCs)

In 2006, Yamanaka and Takahashi first demonstrated the factors necessary for the induced Pluripotent Stem Cells (iPSC) generation. The Yamanaka factors, including Oct3/4 and Sox2 (also Klf4 and c-Myc), represent an important milestone in life sciences and have been widely used in the research and medical fields [33]. iPSCs are a type of pluripotent stem cell that can be generated directly from a somatic cell, usually derived from skin or blood cells, that have been reprogrammed through the introduction of four specific genes ( Oct3/4, Sox2, Myc,and Klf4) encoding transcription factors[34]. Since iPSCs can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease, bringing a promise in the field of regenerative medicine[35].

Related Diseases

Eye Disorders

Mutations in the SOX2 gene have been linked with several eye disorders. An example is bilateral anophthalmia, a severe structural eye deformity. This syndrome is a rare disorder characterized by abnormal development of the eyes and other parts of the body. People with SOX2 anophthalmia syndrome are usually born without eyeballs (anophthalmia), although some individuals have small eyes (microphthalmia); another related disease in this field is septo-optic dysplasia (SOD), a condition characterized by midline and forebrain abnormalities, optic nerve and pituitary hypoplasia[36].

Tumorigenicity

Since these factors are straightly related to pluripotency regulation in stem cells, it has been documented that an aberrant expression of this TF's, together or separately, lead to tumorigenesis, metastasis and even greater recurrence after treatments in different types of cancer [3]. The increased expression of OCT4 was correlated with poorer survival and greater aggressiveness in bladder tumors[3] hepatocellular carcinoma[37], breast[38], pancreas[39], among others. Also, in a recent study, a significant correlation was reported between lower survival of patients with Medulloblastoma, a pedriadic brain tumor, and aberrant expression of the POU5F1 gene[40]. Another study also reported that increased levels of OCT4A in Medulloblastoma cells stimulate their tumorigenic properties, such as cell proliferation and invasion, generation of neurospheres and metastatic capacity, which indicates that these high levels of OCT4A are related with greater tumor aggressiveness[6].

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