Global survey of escape from X inactivation by RNA-sequencing in mouse.

X inactivation equalizes the dosage of gene expression between the sexes, but some genes escape silencing and are thus expressed from both alleles in females. To survey X inactivation and escape in mouse, we performed RNA sequencing in Mus musculus x Mus spretus cells with complete skewing of X inactivation, relying on expression of single nucleotide polymorphisms to discriminate allelic origin. Thirteen of 393 (3.3%) mouse genes had significant expression from the inactive X, including eight novel escape genes. We estimate that mice have significantly fewer escape genes compared with humans. Furthermore, escape genes did not cluster in mouse, unlike the large escape domains in human, suggesting that expression is controlled at the level of individual genes. Our findings are consistent with the striking differences in phenotypes between female mice and women with a single X chromosome--a near normal phenotype in mice versus Turner syndrome and multiple abnormalities in humans. We found that escape genes are marked by the absence of trimethylation at lysine 27 of histone H3, a chromatin modification associated with genes subject to X inactivation. Furthermore, this epigenetic mark is developmentally regulated for some mouse genes.

[1]  Mary Goldman,et al.  The UCSC Genome Browser database: update 2011 , 2010, Nucleic Acids Res..

[2]  L. Carrel,et al.  Dosage compensation and gene expression on the mammalian X chromosome: one plus one does not always equal two , 2009, Chromosome Research.

[3]  Edith Heard,et al.  High-resolution analysis of epigenetic changes associated with X inactivation. , 2009, Genome research.

[4]  M. Oshimura,et al.  Identification of the Chromatin Regions Coated by Non-coding Xist RNA , 2009, Cytogenetic and Genome Research.

[5]  J. Wallingford,et al.  The shroom family proteins play broad roles in the morphogenesis of thickened epithelial sheets , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[6]  C. Bondy.  Turner Syndrome 2008 , 2009, Hormone Research in Paediatrics.

[7]  Andrew M. Jenkinson,et al.  Ensembl 2009 , 2008, Nucleic Acids Res..

[8]  Ting Wang,et al.  The UCSC Genome Browser Database: update 2009 , 2008, Nucleic Acids Res..

[9]  T. Babak,et al.  Global Survey of Genomic Imprinting by Transcriptome Sequencing , 2008, Current Biology.

[10]  L. Carrel,et al.  Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus , 2008, Proceedings of the National Academy of Sciences.

[11]  R. Durbin,et al.  Mapping Quality Scores Mapping Short Dna Sequencing Reads and Calling Variants Using P

, 2022 .

[12]  Jeannie T. Lee,et al.  Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome , 2008, Science.

[13]  A. Bowie,et al.  Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKε‐mediated IRF activation , 2008, The EMBO journal.

[14]  Emmanouil T Dermitzakis,et al.  Large-Scale Population Study of Human Cell Lines Indicates that Dosage Compensation Is Virtually Complete , 2007, PLoS genetics.

[15]  Roland Hetzer,et al.  Sexually dimorphic gene expression in the heart of mice and men , 2007, Journal of Molecular Medicine.

[16]  W. Davies,et al.  The 39,XO mouse as a model for the neurobiology of Turner syndrome and sex-biased neuropsychiatric disorders , 2007, Behavioural Brain Research.

[17]  David Haussler,et al.  The UCSC genome browser database: update 2007 , 2006, Nucleic Acids Res..

[18]  Tatiana Tatusova,et al.  NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins , 2004, Nucleic Acids Res..

[19]  E. Heard,et al.  A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. , 2006, Genes & development.

[20]  A. Arnold,et al.  Tissue-specific expression and regulation of sexually dimorphic genes in mice. , 2006, Genome research.

[21]  C. Disteche,et al.  Dosage compensation in mammals: fine-tuning the expression of the X chromosome. , 2006, Genes & development.

[22]  B. Panning,et al.  The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation , 2006, Nature Cell Biology.

[23]  K. Bomsztyk,et al.  Protocol for the fast chromatin immunoprecipitation (ChIP) method , 2006, Nature Protocols.

[24]  S. Henikoff,et al.  Genome-scale profiling of histone H3.3 replacement patterns , 2005, Nature Genetics.

[25]  Adam S. Raefski,et al.  Identification of a cluster of X-linked imprinted genes in mice. , 2005 .

[26]  H. Willard,et al.  X-inactivation profile reveals extensive variability in X-linked gene expression in females , 2005, Nature.

[27]  David L. Steffen,et al.  The DNA sequence of the human X chromosome , 2005, Nature.

[28]  C. Disteche,et al.  Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development. , 2005, Developmental cell.

[29]  R. Jones.  Identification of a cluster of X-linked imprinted genes in mice , 2005, Nature Genetics.

[30]  J. Gécz,et al.  Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation , 2005, Human Genetics.

[31]  C. Disteche,et al.  Comparative sequence and x-inactivation analyses of a domain of escape in human xp11.2 and the conserved segment in mouse. , 2004, Genome research.

[32]  William Stafford Noble,et al.  Support vector machine classification on the web , 2004, Bioinform..

[33]  E. Hook,et al.  The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism , 2004, Human Genetics.

[34]  N. Brockdorff,et al.  Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. , 2003, Developmental cell.

[35]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in X Inactivation , 2003, Science.

[36]  A. Zinn,et al.  Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF). , 2001, Seminars in reproductive medicine.

[37]  H. Willard,et al.  Chromosomal domains and escape from X inactivation: comparative X inactivation analysis in mouse and human , 2000, Mammalian Genome.

[38]  I. Glass,et al.  The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. , 2000, Human molecular genetics.

[39]  M. Mitchell,et al.  Characterization of genes encoding translation initiation factor eIF-2gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution. , 1998, Human molecular genetics.

[40]  A. Monaco,et al.  The UTX gene escapes X inactivation in mice and humans. , 1998, Human molecular genetics.

[41]  V. Chapman,et al.  Escape from X inactivation of Smcx is preceded by silencing during mouse development , 1998, Nature Genetics.

[42]  C. Disteche,et al.  The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region. , 1998, Human molecular genetics.

[43]  N. Brockdorff,et al.  The mouse Smcx gene exhibits developmental and tissue specific variation in degree of escape from X inactivation. , 1996, Human molecular genetics.

[44]  H. Willard,et al.  Tissue and lineage-specific variation in inactive X chromosome expression of the murine Smcx gene. , 1996, Human molecular genetics.

[45]  J. Mcneil,et al.  XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure , 1996, The Journal of cell biology.

[46]  D. Nickerson,et al.  Peak height variations in automated sequencing of PCR products using Taq dye-terminator chemistry. , 1995, BioTechniques.

[47]  C. Disteche,et al.  Escape from X inactivation in human and mouse. , 1995, Trends in genetics : TIG.

[48]  A. Agulnik,et al.  A novel X gene with a widely transcribed Y-linked homologue escapes X-inactivation in mouse and human. , 1994, Human molecular genetics.

[49]  D. Page,et al.  Turner syndrome: the case of the missing sex chromosome. , 1993, Trends in genetics : TIG.

[50]  T Mori,et al.  [Turner syndrome]. , 1993, Ryoikibetsu shokogun shirizu.

[51]  A. Ashworth,et al.  Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome , 1991, Nature.

[52]  H. Willard,et al.  Characterization of a murine gene expressed from the inactive X chromosome , 1991, Nature.

[53]  Carolyn J. Brown,et al.  A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome , 1991, Nature.

[54]  P. Tam,et al.  Retarded development of XO conceptuses during early pregnancy in the mouse. , 1983, Journal of reproduction and fertility.

[55]  E. P. Evans,et al.  XO monosomy is associated with reduced birthweight and lowered weight gain in the mouse. , 1983, Journal of reproduction and fertility.

[56]  M. Lyon.  Gene Action in the X-chromosome of the Mouse (Mus musculus L.) , 1961, Nature.