OCT4 and SOX2 transcription factors

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=The OCT4-SOX2 mechanism in the nucleosome=
=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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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)<ref name="oct4sox2">PMID:32327602</ref> and both of them act in the DNA removal from the core histones <ref name="um">PMID:25892221</ref>. 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) <ref name="oct4sox2"/> <ref name="um"/> <ref name="oito">PMID:21149679</ref>. The OCT4-POUS and SOX2-HMG DBDs engage major and minor grooves, respectively <ref name="um"/>. The DNA remains attached and straightened around the OCT4 site but is detached around the SOX2 motif <ref name="um"/>.
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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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OCT4 recognizes a partial motif, engaging DNA with its POUS domain, whereas the POUHD is not engaged <ref name="oct4sox2"/>. On free DNA, both POU domains engage the major groove over 8bp on opposite sides of the DNA <ref name="um"/>. SOX2 competes with histones for DNA binding and kinks DNA by ~90° at SHL-6.5 away from the histones <ref name="oito"/>. This is accomplished by intercalation of the SOX2 Phe48 and Met49 ‘wedge’ at the TT base step <ref name="oito"/>. SOX2 kinks the DNA and synergistically with OCT4 releases the DNA from the core histones (Movie1) <ref name="oct4sox2"/>.
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 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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=Gatekeeper for embryonic stem cell pluripotency=
=Gatekeeper for embryonic stem cell pluripotency=
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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].
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The pluripotent identity is ruled by transcriptional factor such as Oct4 and Sox2, that act as key pluripotency regulators among the mammals <ref name="oct4">PMID:25232507</ref>. Oct4 keeps the undifferentiated cells from becoming trophoblast or endoderm <ref name="oct4"/> and Sox2 is critical in the formation of pluripotent epiblast cells <ref name="sox2">PMID:25126380</ref>. 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 <ref name="dois"/> <ref name="treze"/>. 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 name="sox2"/>. 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 <ref name="oct4"/>.
==iPSC/Yamanaka factors==
==iPSC/Yamanaka factors==

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