Molecular Development - X Inactivation - Revision history

Z8600021 at 07:04, 18 Haziran 2020

2020-06-18T07:04:35Z

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	* '''The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist'''{{#pmid:31133748\|PMID31133748}} "The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes {{Xist}} and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other's TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes."

	* '''~~The Implication~~ of ~~Early Chromatin Changes in~~ X ~~Chromosome~~ Inactivation'''{{#pmid:~~30595450~~\|~~PMID30595450~~}}"~~During development, the precise relationships between transcription and chromatin modifications often remain unclear. We use the~~ X chromosome inactivation (XCI) ~~paradigm to explore the implication of chromatin changes in gene~~ silencing~~. Using female mouse embryonic stem cells, we initiate XCI~~ by ~~inducing Xist~~ and ~~then monitor the temporal changes in transcription and chromatin by allele~~-~~specific profiling~~. ~~This reveals histone deacetylation~~ and ~~H2AK119 ubiquitination as the earliest chromatin alterations during XCI. We show that HDAC3 is pre-bound on the~~ X chromosome and ~~that, upon Xist coating, its activity~~ is ~~required for efficient gene silencing~~. ~~We also reveal that first PRC1-associated H2AK119Ub~~ and ~~then PRC2-associated H3K27me3 accumulate initially at large intergenic domains that can then spread into genes only~~ in ~~the context of histone deacetylation~~ and ~~gene~~ silencing. ~~Our results~~ reveal ~~the hierarchy of chromatin events during the initiation~~ of XCI and ~~identify key~~ roles ~~for chromatin~~ in ~~the early steps of transcriptional~~ silencing."		* '''Xist Repeats A and B Account for Two Distinct Phases of X Inactivation Establishment'''{{#pmid:32531209\|PMID32531209}} "X chromosome inactivation (XCI) is a global silencing mechanism by which XX and XY mammals equalize X-linked gene dosages. XCI begins with an establishment phase during which Xist RNA spreads and induces de novo heterochromatinization across a female X chromosome and is followed by a maintenance phase when multiple epigenetic pathways lock down the inactive X (Xi) state. Involvement of Polycomb repressive complexes 1 and 2 in XCI has been intensively studied but with conflicting conclusions regarding their recruitment and role in Xi silencing. Here, we reveal that establishment of XCI has two phases and reconcile the roles that Xist repeats A and B play in gene silencing and Polycomb recruitment. Repeat A initiates both processes, whereas repeat B bolsters or stabilizes them thereafter. Once established, XCI no longer requires repeat A during maintenance. These findings integrate disparate studies and present a unified view of Xist's role in Polycomb-mediated silencing."

	* '''Mammalian X Chromosome Dosage Compensation: Perspectives From the Germ Line'''{{#pmid:29756331\|PMID29756331}} "Sex chromosomes are advantageous to mammals, ~~allowing~~ them ~~to adopt a genetic rather than environmental sex determination system~~. ~~However~~, ~~sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY)~~. ~~This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation~~ and ~~X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face~~ a special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of ~~the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states~~ in ~~germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy~~."

			* '''The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist'''{{#pmid:31133748\|PMID31133748}} "The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes {{Xist}} and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other's TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes."
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			* '''The Implication of Early Chromatin Changes in X Chromosome Inactivation'''{{#pmid:30595450\|PMID30595450}}"During development, the precise relationships between transcription and chromatin modifications often remain unclear. We use the X chromosome inactivation (XCI) paradigm to explore the implication of chromatin changes in gene silencing. Using female mouse embryonic stem cells, we initiate XCI by inducing Xist and then monitor the temporal changes in transcription and chromatin by allele-specific profiling. This reveals histone deacetylation and H2AK119 ubiquitination as the earliest chromatin alterations during XCI. We show that HDAC3 is pre-bound on the X chromosome and that, upon Xist coating, its activity is required for efficient gene silencing. We also reveal that first PRC1-associated H2AK119Ub and then PRC2-associated H3K27me3 accumulate initially at large intergenic domains that can then spread into genes only in the context of histone deacetylation and gene silencing. Our results reveal the hierarchy of chromatin events during the initiation of XCI and identify key roles for chromatin in the early steps of transcriptional silencing."

			* '''Mammalian X Chromosome Dosage Compensation: Perspectives From the Germ Line'''{{#pmid:29756331\|PMID29756331}} "Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy."


	* '''X-chromosome inactivation in female newborns conceived by assisted reproductive technologies'''{{#pmid:24726222\|PMID24726222}} "A total of 185 female newborns, including 60 conceived by intracytoplasmic sperm injection (ICSI), 73 by in vitro fertilization (IVF), and 52 naturally conceived (NC). ...The assisted reproductive technologies of ICSI and IVF do not appear to affect XCI skewing." [[Assisted Reproductive Technology]]		* '''X-chromosome inactivation in female newborns conceived by assisted reproductive technologies'''{{#pmid:24726222\|PMID24726222}} "A total of 185 female newborns, including 60 conceived by intracytoplasmic sperm injection (ICSI), 73 by in vitro fertilization (IVF), and 52 naturally conceived (NC). ...The assisted reproductive technologies of ICSI and IVF do not appear to affect XCI skewing." [[Assisted Reproductive Technology]]

Z8600021 at 06:59, 18 Haziran 2020

2020-06-18T06:59:52Z

← Older revision		Revision as of 17:59, 18 Haziran 2020
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	===Reviews===		===Reviews===
			{{#pmid:32535328}}

	{{#pmid:31900287}}		{{#pmid:31900287}}

Z8600021 at 05:02, 18 Ocak 2020

2020-01-18T05:02:51Z

← Older revision		Revision as of 16:02, 18 Ocak 2020
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	==Tsix==		==Tsix==

	A gene antisense to Xist, hence the name which is Xist backwards, in embryonic stem cells Xist repression occurs and Tsix is upregulated. This is part of the overall process of maintaining pluripotency in these cells. Tsix upregulation depends on the recruitment of another pluripotent marker Rex1, and of the associated factors Klf4 and c-Myc, by the DXPas34 minisatellite associated with the Tsix promoter.{{#pmid:21085182\|PMID21085182}}		A gene antisense to Xist, hence the name which is Xist backwards, in embryonic stem cells Xist repression occurs and Tsix is upregulated. This is part of the overall process of maintaining pluripotency in these cells. Tsix upregulation depends on the recruitment of another pluripotent marker Rex1, and of the associated factors Klf4 and c-Myc, by the DXPas34 minisatellite associated with the Tsix promoter.{{#pmid:21085182\|PMID21085182}}

Z8600021 at 04:50, 18 Ocak 2020

2020-01-18T04:50:51Z

← Older revision		Revision as of 15:50, 18 Ocak 2020
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	==Barr Body==		==Barr Body==
	~~[[File:Murray Barr.jpg\|thumb\|Murray Barr (1908-1995)]]~~
	[[File:Neutrophil EM01.jpg\|500px]]		[[File:Neutrophil EM01.jpg\|500px]]

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	This neutrophil comes from a female donor and one inactivated x chromosome can be found as an extranuclear stretch of heterochromatin. These structures are termed Barr bodies, and in neutrophils “drum sticks.”		This neutrophil comes from a female donor and one inactivated x chromosome can be found as an extranuclear stretch of heterochromatin. These structures are termed Barr bodies, and in neutrophils “drum sticks.”

	~~Named after Murray L. Barr (1908-1995) who with E. Bertram discovered the sex chromatin (Barr body).~~		{{X Inactivation Vignette 2}}



	==X Inactivation (xist) History==		==X Inactivation (xist) History==

Z8600021 at 04:09, 18 Ocak 2020

2020-01-18T04:09:24Z

← Older revision		Revision as of 15:09, 18 Ocak 2020
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	==Barr Body==		==Barr Body==
			[[File:Murray Barr.jpg\|thumb\|Murray Barr (1908-1995)]]
	[[File:Neutrophil EM01.jpg\|500px]]		[[File:Neutrophil EM01.jpg\|500px]]

	A female human neutrophil - Barr body (White arrowhead){{#pmid:22945932\|PMID22945932}}		A female human neutrophil - Barr body (White arrowhead){{#pmid:22945932\|PMID22945932}}
	~~[[[[File:Murray Barr.jpg\|thumb\|Murray Barr (1908-1995)]]~~
	This neutrophil comes from a female donor and one inactivated x chromosome can be found as an extranuclear stretch of heterochromatin. These structures are termed Barr bodies, and in neutrophils “drum sticks.”		This neutrophil comes from a female donor and one inactivated x chromosome can be found as an extranuclear stretch of heterochromatin. These structures are termed Barr bodies, and in neutrophils “drum sticks.”

Z8600021 at 04:08, 18 Ocak 2020

2020-01-18T04:08:34Z

← Older revision		Revision as of 15:08, 18 Ocak 2020
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	A female human neutrophil - Barr body (White arrowhead){{#pmid:22945932\|PMID22945932}}		A female human neutrophil - Barr body (White arrowhead){{#pmid:22945932\|PMID22945932}}
			[[[[File:Murray Barr.jpg\|thumb\|Murray Barr (1908-1995)]]
			This neutrophil comes from a female donor and one inactivated x chromosome can be found as an extranuclear stretch of heterochromatin. These structures are termed Barr bodies, and in neutrophils “drum sticks.”

	~~This neutrophil comes from a female donor and one inactivated x chromosome can be found as an extranuclear stretch of heterochromatin~~. ~~These structures are termed~~ Barr ~~bodies, and in neutrophils “drum sticks~~.”		Named after Murray L. Barr (1908-1995) who with E. Bertram discovered the sex chromatin (Barr body).

Z8600021 at 13:18, 7 Ocak 2020

2020-01-07T13:18:24Z

← Older revision		Revision as of 00:18, 8 Ocak 2020
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	\| [[File:Mark_Hill.jpg\|90px\|left]] {{Most_Recent_Refs}}		\| [[File:Mark_Hill.jpg\|90px\|left]] {{Most_Recent_Refs}}

	Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=X+inactivation ''X inactivation''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Xist ''Xist'']		Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=X+inactivation ''X inactivation''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Xist ''Xist''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Tsix ''Tsix'']

	\|}		\|}

Z8600021 at 13:12, 7 Ocak 2020

2020-01-07T13:12:51Z

← Older revision		Revision as of 00:12, 8 Ocak 2020
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	===Reviews===		===Reviews===
			{{#pmid:31900287}}

	{{#pmid:20573260}}		{{#pmid:20573260}}


	{{#pmid:19815084}}		{{#pmid:19815084}}


	{{#pmid:19802705}}		{{#pmid:19802705}}
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	===Articles===		===Articles===
	{{#pmid:21811421}}		{{#pmid:21811421}}


	{{#pmid:20593031}}		{{#pmid:20593031}}

Z8600021 at 03:52, 23 Haziran 2019

2019-06-23T03:52:36Z

← Older revision		Revision as of 14:52, 23 Haziran 2019
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			* '''The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist'''{{#pmid:31133748\|PMID31133748}} "The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes {{Xist}} and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other's TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes."

	* '''The Implication of Early Chromatin Changes in X Chromosome Inactivation'''{{#pmid:30595450\|PMID30595450}}"During development, the precise relationships between transcription and chromatin modifications often remain unclear. We use the X chromosome inactivation (XCI) paradigm to explore the implication of chromatin changes in gene silencing. Using female mouse embryonic stem cells, we initiate XCI by inducing Xist and then monitor the temporal changes in transcription and chromatin by allele-specific profiling. This reveals histone deacetylation and H2AK119 ubiquitination as the earliest chromatin alterations during XCI. We show that HDAC3 is pre-bound on the X chromosome and that, upon Xist coating, its activity is required for efficient gene silencing. We also reveal that first PRC1-associated H2AK119Ub and then PRC2-associated H3K27me3 accumulate initially at large intergenic domains that can then spread into genes only in the context of histone deacetylation and gene silencing. Our results reveal the hierarchy of chromatin events during the initiation of XCI and identify key roles for chromatin in the early steps of transcriptional silencing."		* '''The Implication of Early Chromatin Changes in X Chromosome Inactivation'''{{#pmid:30595450\|PMID30595450}}"During development, the precise relationships between transcription and chromatin modifications often remain unclear. We use the X chromosome inactivation (XCI) paradigm to explore the implication of chromatin changes in gene silencing. Using female mouse embryonic stem cells, we initiate XCI by inducing Xist and then monitor the temporal changes in transcription and chromatin by allele-specific profiling. This reveals histone deacetylation and H2AK119 ubiquitination as the earliest chromatin alterations during XCI. We show that HDAC3 is pre-bound on the X chromosome and that, upon Xist coating, its activity is required for efficient gene silencing. We also reveal that first PRC1-associated H2AK119Ub and then PRC2-associated H3K27me3 accumulate initially at large intergenic domains that can then spread into genes only in the context of histone deacetylation and gene silencing. Our results reveal the hierarchy of chromatin events during the initiation of XCI and identify key roles for chromatin in the early steps of transcriptional silencing."

Z8600021 at 03:49, 23 Haziran 2019

2019-06-23T03:49:17Z

← Older revision		Revision as of 14:49, 23 Haziran 2019
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	The presence in females of two X chromosome raises the issue of gene dosage, in the case of mammals this is regulated by inactivating one of the X chromosomes.		The presence in females of two X chromosome raises the issue of gene dosage, in the case of mammals this is regulated by inactivating one of the X chromosomes.
	To balance expression with the autosomal chromosomes the dosage imbalance is then adjusted by doubling expression of X-linked genes in both sexes.		To balance expression with the autosomal chromosomes the dosage imbalance is then adjusted by doubling expression of X-linked genes in both sexes.


	In some other species compensation occurs by increasing the expression of X in males. The pattern of which X chromosome is inactivated in cells appears to be random, generating 50% cells expressing Father X, 50% cells expressing Mother X (mosaic pattern). The theory of random X inactivation was first suggested in mice in 1961.{{#pmid:13764598\|PMID13764598}}		In some other species compensation occurs by increasing the expression of X in males. The pattern of which X chromosome is inactivated in cells appears to be random, generating 50% cells expressing Father X, 50% cells expressing Mother X (mosaic pattern). The theory of random X inactivation was first suggested in mice in 1961.{{#pmid:13764598\|PMID13764598}}


	The process of inactivation relies on the '''Xist''' RNA, a 17 kb non-coding RNA, which accumulates on the future inactive X chromosome.		The process of inactivation relies on the '''Xist''' RNA, a 17 kb non-coding RNA, which accumulates on the future inactive X chromosome.


	A second form of X inactivation that occurs only in male meiotic spermatogenesis, meiotic sex chromosome inactivation (MSCI), is not covered in these current notes. MSCI is the process of transcriptional silencing of the X and Y chromosomes.{{#pmid:17329371\|PMID17329371}} X inactivation is not an encoded function and occurs randomly throughout female tissues, this represents a form of {{epigenetics}}.		A second form of X inactivation that occurs only in male meiotic spermatogenesis, meiotic sex chromosome inactivation (MSCI), is not covered in these current notes. MSCI is the process of transcriptional silencing of the X and Y chromosomes.{{#pmid:17329371\|PMID17329371}} X inactivation is not an encoded function and occurs randomly throughout female tissues, this represents a form of {{epigenetics}}.