User:Diogo Andrade Nani - Revision history

Diogo Andrade Nani at 19:09, 24 July 2020

Diogo Andrade Nani — Fri, 24 Jul 2020 19:09:53 GMT

←Older revision		Revision as of 19:09, 24 July 2020
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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 [https://science.sciencemag.org/highwire/filestream/743508/field_highwire_adjunct_files/2/abb0074_s1.mov Movie1]<ref name="oct4sox2"/>.		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 [https://science.sciencemag.org/highwire/filestream/743508/field_highwire_adjunct_files/2/abb0074_s1.mov Movie1]<ref name="oct4sox2"/>.

-
-	[[Image:Figura1.png]]

	'''Figure 1''' - OCT4-SOX2-NCPSHL+6 model<ref name="oct4sox2"/>.		'''Figure 1''' - OCT4-SOX2-NCPSHL+6 model<ref name="oct4sox2"/>.

-	[[Image:Figura2.png]]

	'''Figure 2''' - Domain schematic of OCT4 and SOX2 constructs<ref name="oct4sox2"/>.		'''Figure 2''' - Domain schematic of OCT4 and SOX2 constructs<ref name="oct4sox2"/>.

Diogo Andrade Nani at 23:44, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 23:44:18 GMT

←Older revision		Revision as of 23:44, 21 June 2020
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-	<Structure load='6HT5' size='350' frame='true' align='right' caption='Oct4/Sox2:~~UTF1~~ structure' scene='Insert optional scene name here' />	+	<Structure load='6HT5' size='350' frame='true' align='right' caption='Oct4/Sox2: binding DNA structure' scene='Insert optional scene name here' />
	=OCT4-SOX2=		=OCT4-SOX2=
	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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, 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 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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, forming the complex OCT4-SOX2, which is the main way in which they act, although they are not obligate heterodimers in solution.
Line 22:		Line 22:
	=The OCT4-SOX2 mechanism in the nucleosome=		=The OCT4-SOX2 mechanism in the nucleosome=

-	<Structure load='6t93.pdb' size='350' frame='true' align='right' caption='~~Insert caption here~~' scene='Nucleosome with OCT4-SOX2 motif at SHL-6' />	+	<Structure load='6t93.pdb' size='350' frame='true' align='right' caption='Nucleosome with OCT4-SOX2 motif at SHL-6' scene='Nucleosome with OCT4-SOX2 motif at SHL-6' />

-	<Structure load='6yov.pdb' size='350' frame='true' align='right' caption='~~Insert caption here~~' scene='OCT4-SOX2-bound nucleosome - SHL+6' />	+	<Structure load='6yov.pdb' size='350' frame='true' align='right' caption='OCT4-SOX2-bound nucleosome - SHL+6' scene='OCT4-SOX2-bound nucleosome - SHL+6' />

Diogo Andrade Nani at 23:42, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 23:42:28 GMT

←Older revision		Revision as of 23:42, 21 June 2020
Line 1:		Line 1:
-	<Structure load='6HT5' size='350' frame='true' align='right' caption='~~Insert caption here~~' scene='Insert optional scene name here' />	+	<Structure load='6HT5' size='350' frame='true' align='right' caption='Oct4/Sox2:UTF1 structure' scene='Insert optional scene name here' />
	=OCT4-SOX2=		=OCT4-SOX2=
	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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, 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 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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, forming the complex OCT4-SOX2, which is the main way in which they act, although they are not obligate heterodimers in solution.

Diogo Andrade Nani at 23:40, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 23:40:23 GMT

←Older revision		Revision as of 23:40, 21 June 2020
Line 2:		Line 2:
	=OCT4-SOX2=		=OCT4-SOX2=
	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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, 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 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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, forming the complex OCT4-SOX2, which is the main way in which they act, although they are not obligate heterodimers in solution.
-
-	[[Image:Oct4sox2_intro.png]]

	==OCT4==		==OCT4==

Diogo Andrade Nani at 23:40, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 23:40:01 GMT

←Older revision		Revision as of 23:40, 21 June 2020
Line 1:		Line 1:
		+	<Structure load='6HT5' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />
	=OCT4-SOX2=		=OCT4-SOX2=
	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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, 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 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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, forming the complex OCT4-SOX2, which is the main way in which they act, although they are not obligate heterodimers in solution.

Diogo Andrade Nani at 23:29, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 23:29:20 GMT

←Older revision		Revision as of 23:29, 21 June 2020
Line 2:		Line 2:
	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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, 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 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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, forming the complex OCT4-SOX2, which is the main way in which they act, although they are not obligate heterodimers in solution.

-	[[Image:Oct4sox2_intro]]	+	[[Image:Oct4sox2_intro.png]]

	==OCT4==		==OCT4==

Diogo Andrade Nani at 23:24, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 23:24:53 GMT

←Older revision		Revision as of 23:24, 21 June 2020
Line 1:		Line 1:
	=OCT4-SOX2=		=OCT4-SOX2=
	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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, 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 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 <ref>PMID:16153702</ref><ref>PMID:18555785</ref>, forming the complex OCT4-SOX2, which is the main way in which they act, although they are not obligate heterodimers in solution.
		+
		+	[[Image:Oct4sox2_intro]]

	==OCT4==		==OCT4==

Diogo Andrade Nani at 23:08, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 23:08:28 GMT

←Older revision		Revision as of 23:08, 21 June 2020
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	==SOX2==		==SOX2==
	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.
		+
		+	=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 <ref>PMID:1408763</ref> <ref>PMID:12110702</ref>. Oct4 is present in all stages of embryo development <ref>PMID:9665340</ref> <ref>PMID:8567814</ref> <ref name="dezoito">PMID:23257836</ref>. The Oct4 expression pattern differs between the blastomeres in the same development stage by the protein cytoplasmic localization<ref name="onze">PMID:15695770</ref>. From the unfertilized oocyte to the solid morula no Oct4 protein is observed in the nucleus <ref name="onze"/>. During compaction, Oct4 expression becomes ubiquitous and abundant in the nucleus of all morula blastomeres <ref name="onze"/>. In the blastocyst, the Oct4 mRNA and protein are present in the inner cell mass <ref name="dezoito"/>.
		+
		+	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 <ref name="quatro">PMID:9814708</ref> <ref name="seis">PMID:7958450</ref> <ref name="sete">PMID:11463946</ref> <ref name="oito">PMID:24145198</ref>. 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 <ref name="quatro"/> <ref name="seis"/> <ref name="sete"/> <ref name="oito"/>. During gastrulation, Oct4 is down-regulated and, after day 8 of gestation, it is confined to primordial germ cells <ref name="quatro"/> <ref name="sete"/> <ref>PMID:12528890</ref> <ref>PMID:15486564</ref>.
		+
		+	==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 <ref name="doze">PMID:12514105</ref>. After gastrulation it is predominantly expressed in the central nervous system <ref>PMID:16139372</ref>. 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 <ref name="doze"/>. 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 <ref name="dois">PMID:17515932</ref> <ref name="treze">PMID:18388306</ref>.
		+

	=The OCT4-SOX2 mechanism in the nucleosome=		=The OCT4-SOX2 mechanism in the nucleosome=

Diogo Andrade Nani at 23:02, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 23:02:31 GMT

←Older revision		Revision as of 23:02, 21 June 2020
Line 43:		Line 43:
	==Eye Disorders==		==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<ref>PMID:21396578</ref>.		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<ref>PMID:21396578</ref>.
		+	==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 <ref name="oct4"/>. The increased expression of OCT4 was correlated with poorer survival and greater aggressiveness in bladder tumors<ref name="nimbus1"/> hepatocellular carcinoma<ref>PMID:22824146</ref>, breast<ref>PMID:23596564</ref>, pancreas<ref>PMID:20173672</ref>, 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<ref>PMID:21725800</ref>. 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<ref name="nimbus3"/>.

Diogo Andrade Nani at 22:48, 21 June 2020

Diogo Andrade Nani — Sun, 21 Jun 2020 22:48:40 GMT

←Older revision		Revision as of 22:48, 21 June 2020
Line 43:		Line 43:
	==Eye Disorders==		==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<ref>PMID:21396578</ref>.		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<ref>PMID:21396578</ref>.
-	~~==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 <ref name="oct4"/>. The increased expression of OCT4 was correlated with poorer survival and greater aggressiveness in bladder tumors<ref name="nimbus1"/> hepatocellular carcinoma<ref>PMID:22824146</ref>, breast<ref>PMID:23596564</ref>, pancreas<ref>PMID:20173672</ref>, 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<ref>PMID:21725800<. 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<ref name="nimbus3"/>.	+

	=References=		=References=

	<references />		<references />