Regulation of X-Chromosome Counting by Tsix and Xite Sequences

Abstract Abnormalities in chromosome number have the potential to disrupt the balance of gene expression and thereby decrease organismal fitness and viability. Such abnormalities occur in most solid tumors and also cause severe developmental defects and spontaneous abortions. In contrast to the imbalances in chromosome dose that cause pathologies, the difference in X-chromosome dose used to determine sexual fate across diverse species is well tolerated. Dosage compensation mechanisms have evolved in such species to balance X-chromosome gene expression between the sexes, allowing them to tolerate the difference in X-chromosome dose. This review analyzes the chromosome counting mechanism that tallies X-chromosome number to determine sex (XO male and XX hermaphrodite) in the nematode Caenorhabditis elegans and the associated dosage compensation mechanism that balances X-chromosome gene expression between the sexes. Dissecting the molecular mechanisms underlying X-chromosome counting has revealed how small quantitative differences in intracellular signals can be translated into dramatically different fates. Dissecting the process of X-chromosome dosage compensation has revealed the interplay between chromatin modification and chromosome structure in regulating gene expression over vast chromosomal territories.

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The region 3′ to Xist mediates X chromosome counting and H3 Lys-4 dimethylation within the Xist gene

The EMBO Journal ◽

10.1038/sj.emboj.7600071 ◽

2004 ◽

Vol 23 (3) ◽

pp. 594-604 ◽

Cited By ~ 51

Author(s):

Céline Morey ◽

Pablo Navarro ◽

Emmanuel Debrand ◽

Philip Avner ◽

Claire Rougeulle ◽

...

Keyword(s):

X Chromosome ◽

Xist Gene ◽

Chromosome Counting

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Revisiting the consequences of deleting the X inactivation center

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2102683118 ◽

2021 ◽

Vol 118 (25) ◽

pp. e2102683118

Author(s):

Hao Yin ◽

Chunyao Wei ◽

Jeannie T. Lee

Keyword(s):

Cell Lines ◽

X Chromosome ◽

Mammalian Cells ◽

X Inactivation ◽

Chromosome Counting ◽

Xist Expression ◽

Site Mutation ◽

Noncoding Sequences ◽

Inactivation Center ◽

In Trans

Mammalian cells equalize X-linked dosages between the male (XY) and female (XX) sexes by silencing one X chromosome in the female sex. This process, known as “X chromosome inactivation” (XCI), requires a master switch within the X inactivation center (Xic). The Xic spans several hundred kilobases in the mouse and includes a number of regulatory noncoding genes that produce functional transcripts. Over three decades, transgenic and deletional analyses have demonstrated both the necessity and sufficiency of the Xic to induce XCI, including the steps of X chromosome counting, choice, and initiation of whole-chromosome silencing. One recent study, however, reported that deleting the noncoding sequences of the Xic surprisingly had no effect for XCI and attributed a sufficiency to drive counting to the coding gene, Rnf12/Rlim. Here, we revisit the question by creating independent Xic deletion cell lines. Multiple independent clones carrying heterozygous deletions of the Xic display an inability to up-regulate Xist expression, consistent with a counting defect. This defect is rescued by a second site mutation in Tsix occurring in trans, bypassing the defect in counting. These findings reaffirm the essential nature of noncoding Xic elements for the initiation of XCI.

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Sex Determination in the Drosophila Germline Is Dictated by the Sexual Identity of the Surrounding Soma

Genetics ◽

10.1093/genetics/155.4.1741 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1741-1756 ◽

Cited By ~ 1

Author(s):

J A Waterbury ◽

J I Horabin ◽

D Bopp ◽

P Schedl

Keyword(s):

Sex Determination ◽

Sexual Identity ◽

Signaling Pathway ◽

X Chromosome ◽

Germ Cells ◽

Chromosome Counting ◽

Counting System ◽

Germline Expression ◽

Female Specific ◽

Male Specific

Abstract It has been suggested that sexual identity in the germline depends upon the combination of a nonautonomous somatic signaling pathway and an autonomous X chromosome counting system. In the studies reported here, we have examined the role of the sexual differentiation genes transformer (tra) and doublesex (dsx) in regulating the activity of the somatic signaling pathway. We asked whether ectopic somatic expression of the female products of the tra and dsx genes could feminize the germline of XY animals. We find that TraF is sufficient to feminize XY germ cells, shutting off the expression of male-specific markers and activating the expression of female-specific markers. Feminization of the germline depends upon the constitutively expressed transformer-2 (tra-2) gene, but does not seem to require a functional dsx gene. However, feminization of XY germ cells by TraF can be blocked by the male form of the Dsx protein (DsxM). Expression of the female form of dsx, DsxF, in XY animals also induced germline expression of female markers. Taken together with a previous analysis of the effects of mutations in tra, tra-2, and dsx on the feminization of XX germ cells in XX animals, our findings indicate that the somatic signaling pathway is redundant at the level tra and dsx. Finally, our studies call into question the idea that a cell-autonomous X chromosome counting system plays a central role in germline sex determination.

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