X chromosome inactivation (XCI) is the phenomenon that has been selected during the evolution to balance X-linked gene dosage between XX females and XY males. [1]
X chromosome inactivation (XCI) is the phenomenon that has been selected during the evolution to balance X-linked gene dosage between XX females and XY males. [1]
XCI is usually divided in two phases, the establishment phase when gene silencing is reversible, and maintenance phase when gene silencing becomes irreversible. [2] During the establishment phase of X Chromosome Inactivation (XCI), Xist RNA, the master regulator of this process, is monoallelically upregulated [3] and it spreads in cis along the future inactive X (Xi), relocates to the nuclear periphery. [4] [5] [6] and recruits repressive chromatin-remodelling complexes [7] Among these, Xist recruits proteins of the Polycomb repressive complexes. [8] [9] Whether Xist directly recruits Polycomb repressive complex 2 (PRC2) to the chromatin [10] or this recruitment is the consequence of Xist-mediated changes on the chromatin has been object of intense debate. [11]
Some studies showed that PRC2 components are not associated with Xist RNA or do not interact functionally. [12] [13] [14] [15] However another study has shown by means of mass spectrometry analysis, [16] that two subunits of PRC2 may interact with Xist, although these proteins are also found in other complexes and are not unique components of the PRC2 complex.
PRC2 binds the A-repeat (RepA) of Xist RNA directly and with very high affinity (dissociation constants of 10-100 nanomolar), [17] [18] supporting Xist-mediated recruitment of PRC2 to the X chromosome. However it is not clear whether such interactions occurs in vivo under physiological conditions. [19] Failure to turn up PRC2 proteins in function screens may be due to cells not being able to survive or compete without PRC2 or incomplete screens. Two super resolution microscopy analyses have presented different views from each other. One showed that Xist and PRC2 are spatially separated, [20] while another showed that Xist and PRC2 are tightly linked. [21] It is possible that several mechanisms recruit PRC2 in parallel, including direct Xist-mediated recruitment, adaptor proteins, chromatin changes, RNA pol II exclusion, or PRC1 recruitment. [22] [23] For instance, PRC2 recruitment is linked to PRC1-mediated H2A119 ubiquitination in differentiating embryonic stem cells (ESCs). [24] [25] [26] where PRC1 recruitment is mediated by hnrnpK and Xist repB. [25] [26] In fully differentiated cells, PRC2 recruitment seems to be dependent on Xist RepA. [26] It is possible that alternative and complementary pathways such as phase separation [27] [28] work to establish PRC2 recruitment on the X in different experimental systems and during different stages of development.
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.
A Barr body or X-chromatin is an inactive X chromosome. In species with XY sex-determination, females typically have two X chromosomes, and one is rendered inactive in a process called lyonization. Errors in chromosome separation can also result in male and female individuals with extra X chromosomes. The Lyon hypothesis states that in cells with multiple X chromosomes, all but one are inactivated early in embryonic development in mammals. The X chromosomes that become inactivated are chosen randomly, except in marsupials and in some extra-embryonic tissues of some placental mammals, in which the X chromosome from the sperm is always deactivated.
Heterochromatin is a tightly packed form of DNA or condensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002), and many other papers since, much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.
X-inactivation is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome.
Polycomb-group proteins are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes through modulation of chromatin structure during embryonic development in fruit flies. They derive their name from the fact that the first sign of a decrease in PcG function is often a homeotic transformation of posterior legs towards anterior legs, which have a characteristic comb-like set of bristles.
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.
Polycomb group RING finger protein 2, PCGF2, also known as MEL18 or RNF110, is a protein that in humans is encoded by the PCGF2 gene.
Xist is a non-coding RNA transcribed from the X chromosome of the placental mammals that acts as a major effector of the X-inactivation process. It is a component of the Xic – X-chromosome inactivation centre – along with two other RNA genes and two protein genes.
Long non-coding RNAs are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Given that some lncRNAs have been reported to have the potential to encode small proteins or micro-peptides, the latest definition of lncRNA is a class of RNA molecules of over 200 nucleotides that have no or limited coding capacity. Long intervening/intergenic noncoding RNAs (lincRNAs) are sequences of lncRNA which do not overlap protein-coding genes.
Polycomb group RING finger protein 1, PCGF1, also known as NSPC1 or RNF68 is a RING finger domain protein that in humans is encoded by the PCGF1 gene.
In molecular biology, a Tudor domain is a conserved protein structural domain originally identified in the Tudor protein encoded in Drosophila. The Tudor gene was found in a Drosophila screen for maternal factors that regulate embryonic development or fertility. Mutations here are lethal for offspring, inspiring the name Tudor, as a reference to the Tudor King Henry VIII and the several miscarriages experienced by his wives.
HOTAIR is a human gene located between HOXC11 and HOXC12 on chromosome 12. It is the first example of an RNA expressed on one chromosome that has been found to influence transcription of HOXD cluster posterior genes located on chromosome 2. The sequence and function of HOTAIR is different in human and mouse. Sequence analysis of HOTAIR revealed that it exists in mammals, has poorly conserved sequences and considerably conserved structures, and has evolved faster than nearby HoxC genes. A subsequent study identified HOTAIR has 32 nucleotide long conserved noncoding element (CNE) that has a paralogous copy in HOXD cluster region, suggesting that the HOTAIR conserved sequences predates whole genome duplication events at the root of vertebrate. While the conserved sequence paralogous with HOXD cluster is 32 nucleotide long, the HOTAIR sequence conserved from human to fish is about 200 nucleotide long and is marked by active enhancer features.
PRC2 is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1.
The human KDM2B gene encodes the protein lysine (K)-specific demethylase 2B.
Epigenetics of human development is the study of how epigenetics effects human development.
H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.
Jeannie T. Lee is a Professor of Genetics at Harvard Medical School and the Massachusetts General Hospital, and a Howard Hughes Medical Institute Investigator. She is known for her work on X-chromosome inactivation and for discovering the functions of a new class of epigenetic regulators known as long noncoding RNAs (lncRNAs), including Xist and Tsix.
Polycomb repressive complex 1 (PRC1) is one of the two classes of Polycomb Repressive complexes, the other being PRC2. Polycomb-group proteins play a major role in transcriptional regulation during development. Polycomb Repressive Complexes PRC1 and PRC2 function in the silencing of expression of the Hox gene network involved in development as well as the inactivation of the X chromosome. PRC1 inhibits the activated form of RNA polymerase II preinitiation complex with the use of H3K27me. PRC1 binds to three nucleosomes, this is believed to limit access of transcription factors to the chromatin, and therefore limit gene expression.
Neil Alexander Steven Brockdorff is a Wellcome Trust Principal Research Fellow and professor in the department of biochemistry at the University of Oxford. Brockdorff's research investigates gene and genome regulation in mammalian development. His interests are in the molecular basis of X-inactivation, the process that evolved in mammals to equalise X chromosome gene expression levels in XX females relative to XY males.
X chromosome reactivation (XCR) is the process by which the inactive X chromosome (the Xi) is re-activated in the cells of eutherian female mammals. Therian female mammalian cells have two X chromosomes, while males have only one, requiring X-chromosome inactivation (XCI) for sex-chromosome dosage compensation. In eutherians, XCI is the random inactivation of one of the X chromosomes, silencing its expression. Much of the scientific knowledge currently known about XCR comes from research limited to mouse models or stem cells.
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