Barr body

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Nucleus of a female amniotic fluid cell. Top: Both X-chromosome territories are detected by FISH. Shown is a single optical section made with a confocal microscope. Bottom: Same nucleus stained with DAPI and recorded with a CCD camera. The Barr body is indicated by the arrow, it identifies the inactive X (Xi). Sd4hi-unten-crop.jpg
Nucleus of a female amniotic fluid cell. Top: Both X-chromosome territories are detected by FISH. Shown is a single optical section made with a confocal microscope. Bottom: Same nucleus stained with DAPI and recorded with a CCD camera. The Barr body is indicated by the arrow, it identifies the inactive X (Xi).
Left: DAPI stained female human fibroblast with Barr body (arrow). Right: histone macroH2A1 staining. Arrow points to sex chromatin in DAPI-stained cell nucleus, and to the corresponding sex chromatin site in the histone macroH2A1-staining. BarrBodyBMC Biology2-21-Fig1clip293px.jpg
Left: DAPI stained female human fibroblast with Barr body (arrow). Right: histone macroH2A1 staining. Arrow points to sex chromatin in DAPI-stained cell nucleus, and to the corresponding sex chromatin site in the histone macroH2A1-staining.

A Barr body (named after discoverer Murray Barr) [1] or X-chromatin is an inactive X chromosome. In species with XY sex-determination (including humans), females typically have two X chromosomes, [2] 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. [3] [4] 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. [5]

Contents

In humans with euploidy, a genotypical female (46, XX karyotype) has one Barr body per somatic cell nucleus, while a genotypical male (46, XY) has none. The Barr body can be seen in the interphase nucleus as a darkly staining small mass in contact with the nucleus membrane. Barr bodies can be seen in neutrophils at the rim of the nucleus.

In humans with more than one X chromosome, the number of Barr bodies visible at interphase is always one fewer than the total number of X chromosomes. For example, people with Klinefelter syndrome (47, XXY) have a single Barr body, and people with a 47, XXX karyotype have two Barr bodies.

Mechanism

Someone with two X chromosomes (such as the majority of human females) has only one Barr body per somatic cell, while someone with one X chromosome (such as most human males) has none.

Mammalian X-chromosome inactivation is initiated from the X inactivation centre or Xic, usually found near the centromere. [6] The center contains twelve genes, seven of which code for proteins, five for untranslated RNAs, of which only two are known to play an active role in the X inactivation process, Xist and Tsix . [6] The centre also appears to be important in chromosome counting: ensuring that random inactivation only takes place when two or more X-chromosomes are present. The provision of an extra artificial Xic in early embryogenesis can induce inactivation of the single X found in male cells. [6]

The roles of Xist and Tsix appear to be antagonistic. The loss of Tsix expression on the future inactive X chromosome results in an increase in levels of Xist around the Xic. Meanwhile, on the future active X Tsix levels are maintained; thus the levels of Xist remain low. [7] This shift allows Xist to begin coating the future inactive chromosome, spreading out from the Xic. [2] In non-random inactivation this choice appears to be fixed and current evidence suggests that the maternally inherited gene may be imprinted. [3] Variations in Xi frequency have been reported with age, pregnancy, the use of oral contraceptives, fluctuations in menstrual cycle and neoplasia. [8]

It is thought that this constitutes the mechanism of choice, and allows downstream processes to establish the compact state of the Barr body. These changes include histone modifications, such as histone H3 methylation (i.e. H3K27me3 by PRC2 which is recruited by Xist) [9] and histone H2A ubiquitination, [10] as well as direct modification of the DNA itself, via the methylation of CpG sites. [11] These changes help inactivate gene expression on the inactive X-chromosome and to bring about its compaction to form the Barr body.

Reactivation of a Barr body is also possible, and has been seen in breast cancer patients. [12] One study showed that the frequency of Barr bodies in breast carcinoma were significantly lower than in healthy controls, indicating reactivation of these once inactivated X chromosomes. [12]

See also

Related Research Articles

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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.

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.

<span class="mw-page-title-main">Euchromatin</span> Lightly packed form of chromatin that is enriched in genes

Euchromatin is a lightly packed form of chromatin that is enriched in genes, and is often under active transcription. Euchromatin stands in contrast to heterochromatin, which is tightly packed and less accessible for transcription. 92% of the human genome is euchromatic.

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.

<span class="mw-page-title-main">Sex-chromosome dosage compensation</span> Biological process

Dosage compensation is the process by which organisms equalize the expression of genes between members of different biological sexes. Across species, different sexes are often characterized by different types and numbers of sex chromosomes. In order to neutralize the large difference in gene dosage produced by differing numbers of sex chromosomes among the sexes, various evolutionary branches have acquired various methods to equalize gene expression among the sexes. Because sex chromosomes contain different numbers of genes, different species of organisms have developed different mechanisms to cope with this inequality. Replicating the actual gene is impossible; thus organisms instead equalize the expression from each gene. For example, in humans, female (XX) cells randomly silence the transcription of one X chromosome, and transcribe all information from the other, expressed X chromosome. Thus, human females have the same number of expressed X-linked genes per cell as do human males (XY), both sexes having essentially one X chromosome per cell, from which to transcribe and express genes.

<span class="mw-page-title-main">X-inactivation</span> Inactivation of copies of X chromosome

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.

<span class="mw-page-title-main">Paramutation</span>

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<span class="mw-page-title-main">H2AFY</span> Protein-coding gene in the species Homo sapiens

Core histone macro-H2A.1 is a protein that in humans is encoded by the H2AFY gene.

<span class="mw-page-title-main">XIST</span> Non-coding RNA

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.

Skewed X-chromosome inactivation occurs when the X-inactivation of one X chromosome is favored over the other, leading to an uneven number of cells with each chromosome inactivated. It is usually defined as one allele being found on the active X chromosome in over 75% of cells, and extreme skewing is when over 90% of cells have inactivated the same X chromosome. It can be caused by primary nonrandom inactivation, either by chance due to a small cell pool or directed by genes, or by secondary nonrandom inactivation, which occurs by selection.

<span class="mw-page-title-main">Tsix</span> Non-coding RNA in the species Homo sapiens

Tsix is a non-coding RNA gene that is antisense to the Xist RNA. Tsix binds Xist during X chromosome inactivation. The name Tsix comes from the reverse of Xist, which stands for X-inactive specific transcript.

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<span class="mw-page-title-main">Polycomb recruitment in X chromosome inactivation</span>

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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.

<span class="mw-page-title-main">Neil Brockdorff</span> British biochemist (born 1958)

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.

References

Links to full text articles are provided where access is free, in other cases only the abstract has been linked.

  1. Barr, M. L.; Bertram, E. G. (1949). "A Morphological Distinction between Neurones of the Male and Female, and the Behaviour of the Nucleolar Satellite during Accelerated Nucleoprotein Synthesis". Nature . 163 (4148): 676–677. Bibcode:1949Natur.163..676B. doi:10.1038/163676a0. PMID   18120749. S2CID   4093883.
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  3. 1 2 Brown, C.J., Robinson, W.P., (1997), XIST Expression and X-Chromosome Inactivation in Human Preimplantation Embryos Am. J. Hum. Genet. 61, 5–8 (Full Text PDF)
  4. Lyon, M. F. (1961). "Gene Action in the X-chromosome of the Mouse (Mus musculus L.)". Nature . 190 (4773): 372–373. Bibcode:1961Natur.190..372L. doi:10.1038/190372a0. PMID   13764598. S2CID   4146768.
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  6. 1 2 3 Rougeulle, C.; Avner, P. (2003). "Controlling X-inactivation in mammals: what does the centre hold?". Seminars in Cell & Developmental Biology. 14 (6): 331–340. doi:10.1016/j.semcdb.2003.09.014. PMID   15015740.
  7. Lee, J. T.; Davidow, L. S.; Warshawsky, D. (1999). "Tisx, a gene antisense to Xist at the X-inactivation centre". Nat. Genet. 21 (4): 400–404. doi:10.1038/7734. PMID   10192391. S2CID   30636065.
  8. Sharma, Deepti (January 10, 2018). "Deciphering the Role of the Barr Body in Malignancy". Sultan Qaboos University Medical Journal. 17 (4): 389–397. doi:10.18295/squmj.2017.17.04.003. PMC   5766293 . PMID   29372079.
  9. Heard, E.; Rougeulle, C.; Arnaud, D.; Avner, P.; Allis, C. D. (2001). "Methylation of Histone H3 at Lys-9 Is an Early Mark on the X Chromosome during X Inactivation". Cell. 107 (6): 727–738. doi: 10.1016/S0092-8674(01)00598-0 . PMID   11747809. S2CID   10124177.
  10. de Napoles, M.; Mermoud, J.E.; Wakao, R.; Tang, Y.A.; Endoh, M.; Appanah, R.; Nesterova, T.B.; Silva, J.; Otte, A.P.; Vidal, M.; Koseki, H.; Brockdorff, N. (2004). "Polycomb Group Proteins Ring1A/B Link Ubiquitylation of Histone H2A to Heritable Gene Silencing and X Inactivation". Dev. Cell. 7 (5): 663–676. doi: 10.1016/j.devcel.2004.10.005 . PMID   15525528.
  11. Chadwick, B.P.; Willard, H.F. (2003). "Barring gene expression after XIST: maintaining faculative heterochromatin on the inactive X.". Seminars in Cell & Developmental Biology. 14 (6): 359–367. doi:10.1016/j.semcdb.2003.09.016. PMID   15015743.
  12. 1 2 Natekar, Prashant E.; DeSouza, Fatima M. (2008). "Reactivation of inactive X chromosome in buccal smear of carcinoma of breast". Indian Journal of Human Genetics. 14 (1): 7–8. doi: 10.4103/0971-6866.42320 . ISSN   0971-6866. PMC   2840782 . PMID   20300284.

Further reading