X-chromosome inactivation

Females (XX) carry twice as many X-linked genes on their sex chromosomes as males (XY). How do cells control gene expression to manage this potentially lethal dosage problem? Unlike the gene-poor Y chromosome, the X chromosome contains over 1,000 genes that are essential for proper development and cell viability. However, females carry two copies of the X chromosome, resulting in a potentially toxic double dose of X-linked genes. To correct this imbalance, mammalian females have evolved a unique mechanism of dosage compensation distinct from that used by organisms such as flies and worms. In particular, by way of the process called X-chromosome inactivation (XCI), female mammals transcriptionally silence one of their two Xs in a complex and highly coordinated manner. The inactivated X chromosome then condenses into a compact structure called a Barr body, and it is stably maintained in a silent state . A prime example of X inactivation is in the coat-color patterning of tortoiseshell or calico cats . In cats, the fur pigmentation gene is X-linked, and depending on which copy of the X chromosome each cell chooses to leave active, either an orange or black coat color results. X inactivation only occurs in cells with multiple X chromosomes, which explains why almost all calico cats are female. X inactivation exists in two different forms: random and imprinted. Although both forms utilize the same RNAs and silencing enzymes, they differ in terms of their developmental timing and mechanism of action. Noncoding RNAs and X Inactivation As previously mentioned, RNA plays an important role in X inactivation. Specifically, two noncoding, complementary RNAs—XIST and TSIX—initiate and control the inactivation process. XIST Exists to Silence Slot blot of total cellular RNA isolated from human lymphoblastoid cell lines or mouse-human somatic cell hybrids retaining either the active or inactive human X chromosome, hybridized with the 14A XIST cDNA proble. The probe hybridizes only to RNA samples from cell lines which contain an inactive X chromosome. © 1991 Nature Publishing Group Brown, C. J. et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. XIST, or X-inactive specific transcript, was discovered due to its specific expression from inactive female X chromosomes. This RNA has four unique properties: The XIST gene does not encode a protein but rather produces a 17 kilobase (kb) functional RNA molecule. Hence, it is a noncoding RNA ). XIST RNA is only expressed in cells containing at least two Xs and is not normally expressed in male cells (Figure 2). Higher XIST expression can be seen in cells with more X chromosomes, as a counting mechanism dictates that only one X per cell can remain active. In such cells, XIST is expressed from all supernumerary Xs. XIST RNA remains exclusively in the nucleus and is able to “coat“ the chromosome from which it was produced (Figure 3). Paradoxically, XIST RNA is expressed from an otherwise inactive X chromosome. Research has shown that XIST RNA is both necessary and sufficient for inactivation , and it recruits various silencing protein complexes to label the future inactive X chromosome. Increased XIST expression represents a key initiation event in X inactivation, indicating the central role of this noncoding RNA. TSIX Antagonizes XIST Two side-by-side photomicrographs show a region of DNA coated in Xist RNA. In the photomicrograph at left, the DNA looks like a blue mass of coils against a black background. A small green region, covering one chromosome, is indicated by a white arrow. This green staining corresponds to the XIST coating. The photomicrograph at right shows the image at left in black-and-white, without the staining. The XIST coating is not conspicuous, but the DNA structure is more resolved in this image. So, how is XIST expressed from one X chromosome while it remains silent on the other X? The answer to this question came just several years after the discovery of XIST, when XIST’s antisense partner—TSIX (“XIST“ backwards)—was identified (Lee et al., 1999). The term “antisense“ refers to the fact that TSIX is complementary in sequence to XIST. TSIX is also a long (40 kilobase), noncoding RNA, but it is transcribed in the opposite direction across the entire XIST gene. Like XIST, TSIX only acts on the chromosome that produces it. Moreover, there is an inverse relationship between TSIX and XIST expression: When TSIX transcription is reduced on one X, XIST expression increases and leads to inactivation of that same X chromosome ). In contrast, overexpression of TSIX prevents increases in XIST expression and blocks inactivation in cis or on that same X . These observations suggest that expression of TSIX is required to antagonize XIST on the future active X . #Genetics101 #PaternityTest #Allele #Diploid #meiosis #DNA #autosomal #TurnerSyndrome #NaturalSelection #doubleStrandedDNA #geneticInformatio