The A-repeat links ASF/SF2-dependent Xist RNA processing with random choice during X inactivation

One X chromosome, selected at random, is silenced in each female mammalian cell. Xist encodes a noncoding RNA that influences the probability that the cis-linked X chromosome will be silenced. We found that the A-repeat, a highly conserved element within Xist, is required for the accumulation of spliced Xist RNA. In addition, the A-repeat is necessary for X-inactivation to occur randomly. In combination, our data suggest that normal Xist RNA processing is important in the regulation of random X-inactivation. We propose that modulation of Xist RNA processing may be part of the stochastic process that determines which X chromosome will be inactivated.

[1]  Jinhua Wang,et al.  ESEfinder: a web resource to identify exonic splicing enhancers , 2003, Nucleic Acids Res..

[2]  T. Ohhata,et al.  A proximal conserved repeat in the Xist gene is essential as a genomic element for X-inactivation in mouse , 2009, Development.

[3]  B. Panning,et al.  An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity , 2008, Cell.

[4]  C. Senner,et al.  Dicer regulates Xist promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a , 2008, Epigenetics & Chromatin.

[5]  Jeannie T. Lee Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation , 2002, Nature Genetics.

[6]  Jeannie T. Lee,et al.  Tsix, a gene antisense to Xist at the X-inactivation centre , 1999, Nature Genetics.

[7]  P. Avner,et al.  2-D Structure of the A Region of Xist RNA and Its Implication for PRC2 Association , 2010, PLoS biology.

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

[9]  R. Jaenisch,et al.  Role of the Xist Gene in X Chromosome Choosing , 1998, Cell.

[10]  Alan Ashworth,et al.  Xist has properties of the X-chromosome inactivation centre , 1997, Nature.

[11]  J. Sabina,et al.  Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure. , 1999, Journal of molecular biology.

[12]  R. Jaenisch,et al.  DNA hypomethylation can activate Xist expression and silence X-linked genes. , 1996, Genes & development.

[13]  B. Panning,et al.  XIST RNA exhibits nuclear retention and exhibits reduced association with the export factor TAP/NXF1 , 2007, Chromosoma.

[14]  Rudolf Jaenisch,et al.  Chromosomal silencing and localization are mediated by different domains of Xist RNA , 2002, Nature Genetics.

[15]  N. Brockdorff,et al.  Skewing X chromosome choice by modulating sense transcription across the Xist locus. , 2003, Genes & development.

[16]  Carolyn J. Brown,et al.  The human XIST gene: Analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus , 1992, Cell.

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

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

[19]  Edith Heard,et al.  Differential Histone H3 Lys-9 and Lys-27 Methylation Profiles on the X Chromosome , 2004, Molecular and Cellular Biology.

[20]  G. Kay,et al.  SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation , 2008, Nature Genetics.

[21]  Neil Brockdorff,et al.  Stabilization of Xist RNA Mediates Initiation of X Chromosome Inactivation , 1997, Cell.

[22]  R. Jaenisch,et al.  Xist-deficient mice are defective in dosage compensation but not spermatogenesis. , 1997, Genes & development.

[23]  C. Epstein,et al.  X–chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro , 1978, Nature.

[24]  Susanna Mlynarczyk-Evans,et al.  X Chromosomes Alternate between Two States prior to Random X-Inactivation , 2006, PLoS biology.

[25]  R. Jaenisch,et al.  Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation , 1999, Nature Genetics.

[26]  A. Krainer,et al.  Listening to silence and understanding nonsense: exonic mutations that affect splicing , 2002, Nature Reviews Genetics.

[27]  R. Jaenisch,et al.  A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. , 2000, Molecular cell.

[28]  Y. Hoki,et al.  Tsix defective in splicing is competent to establish Xist silencing , 2006, Development.

[29]  R. Jaenisch,et al.  Antisense Transcription through theXist Locus Mediates Tsix Function in Embryonic Stem Cells , 2001, Molecular and Cellular Biology.

[30]  Xiang-Dong Fu,et al.  Dephosphorylation-dependent sorting of SR splicing factors during mRNP maturation. , 2005, Molecular cell.

[31]  Y. Hoki,et al.  Tsix silences Xist through modification of chromatin structure. , 2005, Developmental cell.

[32]  Dmitri A. Nusinow,et al.  The histone domain of macroH2A1 contains several dispersed elements that are each sufficient to direct enrichment on the inactive X chromosome. , 2007, Journal of molecular biology.

[33]  R. Jaenisch,et al.  X chromosome choice occurs independently of asynchronous replication timing , 2005, The Journal of cell biology.

[34]  J. Steitz,et al.  A molecular link between SR protein dephosphorylation and mRNA export. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[35]  F. Grosveld,et al.  X Inactivation Counting and Choice Is a Stochastic Process: Evidence for Involvement of an X-Linked Activator , 2008, Cell.

[36]  R. B. Redmon,et al.  Identity , 2021, Notre Dame J. Formal Log..

[37]  S. Rastan,et al.  Evidence that random and imprinted Xist expression is controlled by preemptive methylation , 1994, Cell.

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

[39]  R. Jaenisch,et al.  X Chromosome Inactivation Is Mediated by Xist RNA Stabilization , 1997, Cell.

[40]  Joost Gribnau,et al.  X inactivation Xplained. , 2007, Current opinion in genetics & development.

[41]  C. Allis,et al.  Methylation of Histone H3 at Lys-9 Is an Early Mark on the X Chromosome during X Inactivation , 2001, Cell.

[42]  P. Avner,et al.  X-chromosome inactivation: counting, choice and initiation , 2001, Nature Reviews Genetics.

[43]  Jeannie T. Lee,et al.  A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization. , 2006, Molecular cell.

[44]  Jeannie T. Lee,et al.  Targeted Mutagenesis of Tsix Leads to Nonrandom X Inactivation , 1999, Cell.

[45]  L. Steinmetz,et al.  Antisense artifacts in transcriptome microarray experiments are resolved by actinomycin D , 2007, Nucleic acids research.

[46]  J. Lee,et al.  Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[47]  B. Panning,et al.  Condensin complexes regulate mitotic progression and interphase chromatin structure in embryonic stem cells , 2010, The Journal of cell biology.

[48]  M. Zuker,et al.  "Well-determined" regions in RNA secondary structure prediction: analysis of small subunit ribosomal RNA. , 1995, Nucleic acids research.