OCT4 and SOX2 transcription factors
From Proteopedia
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The SOX/Sox (SRY homology box) family of proteins comprises 20 individual members in man and mouse <ref>PMID:12194848</ref>, 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 <ref>PMID:11071752</ref><ref>PMID:31477842</ref>. 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)<ref>PMID:18059259</ref>. SOX2 significantly often imposes transcription modulatory in conjunction with co-factors, such as Oct3/4. | The SOX/Sox (SRY homology box) family of proteins comprises 20 individual members in man and mouse <ref>PMID:12194848</ref>, 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 <ref>PMID:11071752</ref><ref>PMID:31477842</ref>. 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)<ref>PMID:18059259</ref>. SOX2 significantly often imposes transcription modulatory in conjunction with co-factors, such as Oct3/4. | ||
OCT3/4 in ES cells | OCT3/4 in ES cells | ||
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| - | =The OCT4-SOX2 mechanism in the nucleosome= | ||
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| - | 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". The OCT4-SOX2 binds in the SHL-6 site (Fig 1) and both of them act in the DNA removal from the core histones [ref1]. 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) [refs 1, 8]. The OCT4-POUS and SOX2-HMG DBDs engage major and minor grooves, respectively [ref1]. The DNA remains attached and straightened around the OCT4 site but is detached around the SOX2 motif [ref1]. | ||
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| - | OCT4 recognizes a partial motif, engaging DNA with its POUS domain, whereas the POUHD is not engaged. On free DNA, both POU domains engage the major groove over 8bp on opposite sides of the DNA [ref1]. SOX2 competes with histones for DNA binding and kinks DNA by ~90° at SHL-6.5 away from the histones [ref. 8]. This is accomplished by intercalation of the SOX2 Phe48 and Met49 ‘wedge’ at the TT base step [ref 8]. SOX2 kinks the DNA and synergistically with OCT4 releases the DNA from the core histones [movie1]. | ||
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| - | Figure 1 - Extracted from the article '''Mechanisms of OCT4-SOX2 motif readout on nucleosomes''' (Alicia K. Michael et al., 2020). (B) OCT4-SOX2-NCPSHL+6 model. (C) Details of SOX2-induced DNA kink. | ||
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| - | Figure 2 - Extracted from the article '''Mechanisms of OCT4-SOX2 motif readout on nucleosomes''' (Alicia K. Michael et al., 2020). (A) Domain schematic of OCT4 and SOX2 constructs. | ||
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| - | Movie 1 - Extracted from the Supplementary Materials for the article '''Mechanisms of OCT4-SOX2 motif readout on nucleosomes''' (Alicia K. Michael et al., 2020). OCT4-SOX2 binding at SHL-6 removes DNA from the histone core. A morph video modelling the structural change induced in the nucleosome upon OCT4-SOX2 binding at SHL-6. Morph is between the DNA of the NCP-SHL-6 and OCT4-SOX2-NCP-SHL-6 models. | ||
=Embryonic Expression= | =Embryonic Expression= | ||
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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 [rev sox2 - 12]. After gastrulation it is predominantly expressed in the central nervous system [rev sox2 - 22]. 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 [rev sox2 - 12]. 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 [rev sox2 - 2, 13]. | 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 [rev sox2 - 12]. After gastrulation it is predominantly expressed in the central nervous system [rev sox2 - 22]. 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 [rev sox2 - 12]. 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 [rev sox2 - 2, 13]. | ||
| + | =The OCT4-SOX2 mechanism in the nucleosome= | ||
| + | |||
| + | 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". The OCT4-SOX2 binds in the SHL-6 site (Fig 1) and both of them act in the DNA removal from the core histones [ref1]. 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) [refs 1, 8]. The OCT4-POUS and SOX2-HMG DBDs engage major and minor grooves, respectively [ref1]. The DNA remains attached and straightened around the OCT4 site but is detached around the SOX2 motif [ref1]. | ||
| + | |||
| + | OCT4 recognizes a partial motif, engaging DNA with its POUS domain, whereas the POUHD is not engaged. On free DNA, both POU domains engage the major groove over 8bp on opposite sides of the DNA [ref1]. SOX2 competes with histones for DNA binding and kinks DNA by ~90° at SHL-6.5 away from the histones [ref. 8]. This is accomplished by intercalation of the SOX2 Phe48 and Met49 ‘wedge’ at the TT base step [ref 8]. SOX2 kinks the DNA and synergistically with OCT4 releases the DNA from the core histones [movie1]. | ||
| + | |||
| + | Figure 1 - Extracted from the article '''Mechanisms of OCT4-SOX2 motif readout on nucleosomes''' (Alicia K. Michael et al., 2020). (B) OCT4-SOX2-NCPSHL+6 model. (C) Details of SOX2-induced DNA kink. | ||
| + | |||
| + | Figure 2 - Extracted from the article '''Mechanisms of OCT4-SOX2 motif readout on nucleosomes''' (Alicia K. Michael et al., 2020). (A) Domain schematic of OCT4 and SOX2 constructs. | ||
| + | |||
| + | Movie 1 - Extracted from the Supplementary Materials for the article '''Mechanisms of OCT4-SOX2 motif readout on nucleosomes''' (Alicia K. Michael et al., 2020). OCT4-SOX2 binding at SHL-6 removes DNA from the histone core. A morph video modelling the structural change induced in the nucleosome upon OCT4-SOX2 binding at SHL-6. Morph is between the DNA of the NCP-SHL-6 and OCT4-SOX2-NCP-SHL-6 models. | ||
| - | =Gatekeeper for | + | =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 [rev oct4]. Oct4 keeps the undifferentiated cells from becoming trophoblast or endoderm [rev oct4] and Sox2 is critical in the formation of pluripotent epiblast cells [artg sox2]. 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 [ artigo sox2 - 2,13]. 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 [ref artigo sox2]. They activate the transcription of genes involved in the self renewal of embryonic stem cells [ref revisao oct4]. Besides, they bind themselves to the promoters of their own genes activating them [revisao oct4]. | The pluripotent identity is ruled by transcriptional factor such as Oct4 and Sox2, that act as key pluripotency regulators among the mammals [rev oct4]. Oct4 keeps the undifferentiated cells from becoming trophoblast or endoderm [rev oct4] and Sox2 is critical in the formation of pluripotent epiblast cells [artg sox2]. 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 [ artigo sox2 - 2,13]. 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 [ref artigo sox2]. They activate the transcription of genes involved in the self renewal of embryonic stem cells [ref revisao oct4]. Besides, they bind themselves to the promoters of their own genes activating them [revisao oct4]. | ||
Revision as of 15:35, 17 June 2020
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