Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster

Deng, Xinxian; Hiatt, Joseph; Nguyen, Di Kim; Ercan, Sevinç; Sturgill, David; Hillier, LaDeana W.; Schlesinger, Felix; Davis, Carrie A.; Reinke, V; Gingeras, T; Shendure, Jay; Waterston, Robert H.; Oliver, Brian; Lieb, Jason D.; Distèche, Christine M.

doi:10.1038/ng.948

Cited by 261 publications

(393 citation statements)

References 62 publications

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“…To equalize the expression of the X chromosome between hermaphrodites (which have two X chromosomes) and males (which have only a single X chromosome), the expression of genes on the X chromosomes in hermaphrodites is reduced by twofold in a process known as dosage compensation (for review, see Meyer 2010). This is in contrast to dosage compensation in mammals where in cells carrying two X chromosomes, one of the X chromosomes is inactivated while dosage-sensitive genes in the other are upregulated (Deng et al 2011). A key component of the dosage-compensation machinery in C. elegans is the dosage compensation complex (DCC), which is structurally similar to the condensin complex that can induce structural changes to DNA (Sharma et al 2014;Lau and Csankovszki 2015).…”

Section: Features Of C Elegans Chromosome Organizationmentioning

confidence: 57%

Cell Biology of theCaenorhabditis elegansNucleus

Cohen-Fix

Askjaer

2017

Genetics

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Studies on the Caenorhabditis elegans nucleus have provided fascinating insight to the organization and activities of eukaryotic cells. Being the organelle that holds the genetic blueprint of the cell, the nucleus is critical for basically every aspect of cell biology. The stereotypical development of C. elegans from a one cell-stage embryo to a fertile hermaphrodite with 959 somatic nuclei has allowed the identification of mutants with specific alterations in gene expression programs, nuclear morphology, or nuclear positioning. Moreover, the early C. elegans embryo is an excellent model to dissect the mitotic processes of nuclear disassembly and reformation with high spatiotemporal resolution. We review here several features of the C. elegans nucleus, including its composition, structure, and dynamics. We also discuss the spatial organization of chromatin and regulation of gene expression and how this depends on tight control of nucleocytoplasmic transport. Finally, the extensive connections of the nucleus with the cytoskeleton and their implications during development are described. Most processes of the C. elegans nucleus are evolutionarily conserved, highlighting the relevance of this powerful and versatile model organism to human biology.KEYWORDS Caenorhabditis elegans; chromatin; gene expression; lamin; LEM-domain proteins; LINC; P granule; nuclear pore complex; nuclear envelope; nucleocytoplasmic transport; nucleolus; WormBook TABLE OF CONTENTSAbstract 25 C. elegans as a model system to study cell biology of the nucleus 26 Structural components of the nucleus 27

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Section: Features Of C Elegans Chromosome Organizationmentioning

confidence: 57%

Cell Biology of theCaenorhabditis elegansNucleus

Cohen-Fix

Askjaer

2017

Genetics

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“…The association of methylation with gene expression is also suggested by the observation that the X chromosome is more heavily methylated than all other chromosomes. In Drosophila, the X chromosome is subject to gene dosage compensation through the up-regulation of X-linked genes in males (Baker et al 1994;Deng et al 2011). Although it is tempting to speculate that the higher density of methylation on the X chromosome is involved in dosage compensation, it is not clear how methylation would contribute to the process.…”

Section: Discussionmentioning

confidence: 99%

Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity

Takayama¹,

Dhahbi²,

et al. 2014

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Cytosine methylation in the genome of Drosophila melanogaster has been elusive and controversial: Its location and function have not been established. We have used a novel and highly sensitive genomewide cytosine methylation assay to detect and map genome methylation in stage 5 Drosophila embryos. The methylation we observe with this method is highly localized and strand asymmetrical, limited to regions covering ∼1% of the genome, dynamic in early embryogenesis, and concentrated in specific 5-base sequence motifs that are CA- and CT-rich but depleted of guanine. Gene body methylation is associated with lower expression, and many genes containing methylated regions have developmental or transcriptional functions. The only known DNA methyltransferase in Drosophila is the DNMT2 homolog MT2, but lines deficient for MT2 retain genomic methylation, implying the presence of a novel methyltransferase. The association of methylation with a lower expression of specific developmental genes at stage 5 raises the possibility that it participates in controlling gene expression during the maternal-zygotic transition.

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“…However, RNA sequencing (RNA-Seq) revealed an X:AA expression ratio of ∼0.5, refuting Ohno's hypothesis (12). A number of authors subsequently noted that the fraction of inactive genes is greater in X than in autosomes and that X:AA ∼1 when only active genes are considered (14)(15)(16)(17). We suggested that the extra inactive genes in X originated from the most weakly expressed genes in X as a consequence of Y degeneration, and that X:AA ∼0.5 when appropriate sets of active genes are compared (13).…”

mentioning

confidence: 92%

Expression reduction in mammalian X chromosome evolution refutes Ohno’s hypothesis of dosage compensation

Lin

Xing

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

177

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Susumu Ohno proposed in 1967 that, during the origin of mammalian sex chromosomes from a pair of autosomes, per-allele expression levels of X-linked genes were doubled to compensate for the degeneration of their Y homologs. This conjecture forms the foundation of the current evolutionary model of sex chromosome dosage compensation, but has been tested in mammals only indirectly via a comparison of expression levels between X-linked and autosomal genes in the same genome. The test results have been controversial, because examinations of different gene sets led to different conclusions that either support or refute Ohno's hypothesis. Here we resolve this uncertainty by directly comparing mammalian X-linked genes with their one-to-one orthologs in species that diverged before the origin of the mammalian sex chromosomes. Analyses of RNA sequencing data and proteomic data provide unambiguous evidence for expression halving (i.e., no change in per-allele expression level) of X-linked genes during evolution, with the exception of only ∼5% of genes that encode members of large protein complexes. We conclude that Ohno's hypothesis is rejected for the vast majority of genes, reopening the search for the evolutionary force driving the origin of chromosomewide X inactivation in female mammals.

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Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster

Cited by 261 publications

References 62 publications

Cell Biology of theCaenorhabditis elegansNucleus

Cell Biology of theCaenorhabditis elegansNucleus

Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity

Expression reduction in mammalian X chromosome evolution refutes Ohno’s hypothesis of dosage compensation

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