X Inactivation and Escape: Epigenetic and Structural Features

X inactivation represents a complex multi-layer epigenetic mechanism that profoundly modifies chromatin composition and structure of one X chromosome in females. The heterochromatic inactive X chromosome adopts a unique 3D bipartite structure and a location close to the nuclear periphery or the nucleolus. X-linked lncRNA loci and their transcripts play important roles in the recruitment of proteins that catalyze chromatin and DNA modifications for silencing, as well as in the control of chromatin condensation and location of the inactive X chromosome. A subset of genes escapes X inactivation, raising questions about mechanisms that preserve their expression despite being embedded within heterochromatin. Escape gene expression differs between males and females, which can lead to physiological sex differences. We review recent studies that emphasize challenges in understanding the role of lncRNAs in the control of epigenetic modifications, structural features and nuclear positioning of the inactive X chromosome. Second, we highlight new findings about the distribution of genes that escape X inactivation based on single cell studies, and discuss the roles of escape genes in eliciting sex differences in health and disease.

[1]  K. Tang,et al.  Conjoint analysis of lncRNA and mRNA expression in rotator cuff tendinopathy , 2020, Annals of translational medicine.

[2]  W. Lijuan,et al.  The Differential Expression of Long Noncoding RNAs in Type 2 Diabetes Mellitus and Latent Autoimmune Diabetes in Adults , 2020, International journal of endocrinology.

[3]  M. Primig,et al.  Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations during Mammalian Development , 2019, Cells.

[4]  C. Syrett,et al.  When the balance is broken: X‐linked gene dosage from two X chromosomes and female‐biased autoimmunity , 2019, Journal of leukocyte biology.

[5]  K. Kristiansen,et al.  Single‐cell RNA‐seq reveals distinct dynamic behavior of sex chromosomes during early human embryogenesis , 2019, Molecular reproduction and development.

[6]  William Stafford Noble,et al.  Trans- and cis-acting effects of the lncRNA Firre on epigenetic and structural features of the inactive X chromosome , 2019, bioRxiv.

[7]  J. Rinn,et al.  The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis , 2019, Nature Communications.

[8]  P. Avner,et al.  Phase separation drives X-chromosome inactivation: a hypothesis , 2019, Nature Structural & Molecular Biology.

[9]  Zachary D. Smith,et al.  In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation , 2019, bioRxiv.

[10]  M. Guttman,et al.  The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist , 2019, Nature Genetics.

[11]  Huaiyang Jiang,et al.  A high-resolution X chromosome copy-number variation map in fertile females and women with primary ovarian insufficiency , 2019, Genetics in Medicine.

[12]  Sarmistha Banerjee,et al.  Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases. , 2019, JCI insight.

[13]  Andrea J. Kriz,et al.  Xist Deletional Analysis Reveals an Interdependency between Xist RNA and Polycomb Complexes for Spreading along the Inactive X. , 2019, Molecular cell.

[14]  M. Nielsen,et al.  Epigenetics and genomics in Turner syndrome , 2019, American journal of medical genetics. Part C, Seminars in medical genetics.

[15]  B. Payer,et al.  PRDM14 controls X-chromosomal and global epigenetic reprogramming of H3K27me3 in migrating mouse primordial germ cells , 2019, Epigenetics & Chromatin.

[16]  Wan-Sheng Liu.  Mammalian Sex Chromosome Structure, Gene Content, and Function in Male Fertility. , 2019, Annual review of animal biosciences.

[17]  E. Heard,et al.  Nuclear positioning and pairing of X-chromosome inactivation centers are not primary determinants during initiation of random X-inactivation , 2019, Nature Genetics.

[18]  P. Cramer,et al.  The Implication of Early Chromatin Changes in X Chromosome Inactivation , 2019, Cell.

[19]  J. Dekker,et al.  The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome , 2019, Nature Communications.

[20]  Chong-Jian Chen,et al.  Kinetics of Xist-induced gene silencing can be predicted from combinations of epigenetic and genomic features , 2019, bioRxiv.

[21]  J. Dekker,et al.  The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome , 2019, Nature Communications.

[22]  Emily J. Davis,et al.  Female XX sex chromosomes increase survival and extend lifespan in aging mice , 2018, Aging cell.

[23]  M. Linial,et al.  Human genes escaping X-inactivation revealed by single cell expression data , 2018, BMC Genomics.

[24]  T. Kwon,et al.  Physiological effects of KDM5C on neural crest migration and eye formation during vertebrate development , 2018, Epigenetics & Chromatin.

[25]  N. Brockdorff,et al.  Systematic allelic analysis defines the interplay of key pathways in X chromosome inactivation , 2018, Nature Communications.

[26]  E. Heard,et al.  X-Chromosome Inactivation: A Crossroads Between Chromosome Architecture and Gene Regulation. , 2018, Annual review of genetics.

[27]  T. Dudding-Byth,et al.  IQSEC2 mutation update and review of the female‐specific phenotype spectrum including intellectual disability and epilepsy , 2018, Human mutation.

[28]  G. Kay,et al.  Smchd1 Targeting to the Inactive X Is Dependent on the Xist-HnrnpK-PRC1 Pathway. , 2018, Cell reports.

[29]  A. Arnold,et al.  Sexual Inequality in the Cancer Cell. , 2018, Cancer research.

[30]  K. Nagao,et al.  Role of SmcHD1 in establishment of epigenetic states required for the maintenance of the X-inactivated state in mice , 2018, Development.

[31]  J. S. Pedersen,et al.  DNA hypermethylation and differential gene expression associated with Klinefelter syndrome , 2018, Scientific Reports.

[32]  William S. DeWitt,et al.  A Single-Cell Atlas of In Vivo Mammalian Chromatin Accessibility , 2018, Cell.

[33]  Carolyn J. Brown,et al.  The eXceptional nature of the X chromosome. , 2018, Human molecular genetics.

[34]  Andrea J. Kriz,et al.  Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape , 2018, Nature Communications.

[35]  Brian D. Bennett,et al.  Dosage compensation and DNA methylation landscape of the X chromosome in mouse liver , 2018, Scientific Reports.

[36]  Jeannie T. Lee,et al.  SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X , 2018, Cell.

[37]  Prabhakar R. Gudla,et al.  Effects of human sex chromosome dosage on spatial chromosome organization , 2018, bioRxiv.

[38]  S. Kaneko,et al.  X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism , 2018, Science Advances.

[39]  Osagie G. Izuogu,et al.  Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular , 2018, BMC Genomics.

[40]  J. Rinn,et al.  A TAD boundary is preserved upon deletion of the CTCF-rich Firre locus , 2018, Nature Communications.

[41]  S. Antonarakis,et al.  Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts , 2018, Proceedings of the National Academy of Sciences.

[42]  Andrea J. Korecki,et al.  Human cis-acting elements regulating escape from X-chromosome inactivation function in mouse , 2018, Human molecular genetics.

[43]  Nicolas L. Fawzi,et al.  Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation. , 2018, Molecular cell.

[44]  A. Canivet,et al.  TLR7 escapes X chromosome inactivation in immune cells , 2018, Science Immunology.

[45]  N. Brockdorff,et al.  hnRNPK Recruits PCGF3/5-PRC1 to the Xist RNA B-Repeat to Establish Polycomb-Mediated Chromosomal Silencing , 2017, Molecular cell.

[46]  Yang Shi,et al.  Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons. , 2017, Cell reports.

[47]  C. Disteche,et al.  Structural aspects of the inactive X chromosome , 2017, Philosophical Transactions of the Royal Society B: Biological Sciences.

[48]  M. Vibranovski,et al.  Early X chromosome inactivation during human preimplantation development revealed by single-cell RNA-sequencing , 2017, Scientific Reports.

[49]  William Stafford Noble,et al.  Orientation-dependent Dxz4 contacts shape the 3D structure of the inactive X chromosome , 2017, Nature Communications.

[50]  A. Barski,et al.  Xist RNA repeat E is essential for ASH2L recruitment to the inactive X and regulates histone modifications and escape gene expression , 2017, PLoS genetics.

[51]  C. Disteche,et al.  Allele-specific non-CG DNA methylation marks domains of active chromatin in female mouse brain , 2017, Proceedings of the National Academy of Sciences.

[52]  Andrew J. Dunford,et al.  Tumor suppressor genes that escape from X-inactivation contribute to cancer sex bias , 2016, Nature Genetics.

[53]  David J. Arenillas,et al.  YY1 binding association with sex-biased transcription revealed through X-linked transcript levels and allelic binding analyses , 2016, Scientific Reports.

[54]  Noah Ollikainen,et al.  Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing , 2016, Science.

[55]  Jesse M. Engreitz,et al.  Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression , 2016, Nature Reviews Molecular Cell Biology.

[56]  T. Ørntoft,et al.  Widespread DNA hypomethylation and differential gene expression in Turner syndrome , 2016, Scientific Reports.

[57]  Beryl B. Cummings,et al.  Landscape of X chromosome inactivation across human tissues , 2016, Nature.

[58]  Leming Shi,et al.  Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation , 2016, Genome research.

[59]  C. Disteche.  Dosage compensation of the sex chromosomes and autosomes. , 2016, Seminars in cell & developmental biology.

[60]  Neva C. Durand,et al.  Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture , 2016, Proceedings of the National Academy of Sciences.

[61]  Howard Y. Chang,et al.  Structural organization of the inactive X chromosome in the mouse , 2016, Nature.

[62]  L. McCullough,et al.  Stroke sensitivity in the aged: sex chromosome complement vs. gonadal hormones , 2016, Aging.

[63]  Carolyn J. Brown,et al.  Escape Artists of the X Chromosome. , 2016, Trends in genetics : TIG.

[64]  Michael C. Rusch,et al.  Cancer-associated DDX3X mutations drive stress granule assembly and impair global translation , 2016, Scientific Reports.

[65]  Rickard Sandberg,et al.  Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos , 2016, Cell.

[66]  J. Gribnau,et al.  New Xist-Interacting Proteins in X-Chromosome Inactivation , 2016, Current Biology.

[67]  Chinmay J. Shukla,et al.  Function and evolution of local repeats in the Firre locus , 2016, Nature Communications.

[68]  M. Atchison,et al.  Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X , 2016, Proceedings of the National Academy of Sciences.

[69]  Andrew Thompson,et al.  A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation. , 2016, Cell reports.

[70]  Peter H. L. Krijger,et al.  CTCF Binding Polarity Determines Chromatin Looping. , 2015, Molecular cell.

[71]  C. Disteche,et al.  X-chromosome inactivation and escape , 2015, Journal of Genetics.

[72]  W. Linehan,et al.  Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC) , 2015, PloS one.

[73]  R. Sandberg,et al.  Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation , 2015, Nature Reviews Genetics.

[74]  N. Brockdorff,et al.  Independent Mechanisms Target SMCHD1 to Trimethylated Histone H3 Lysine 9-Modified Chromatin and the Inactive X Chromosome , 2015, Molecular and Cellular Biology.

[75]  Marco Y. Hein,et al.  A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation , 2015, Cell.

[76]  William Stafford Noble,et al.  Bipartite structure of the inactive mouse X chromosome , 2015, Genome Biology.

[77]  S. Kushner,et al.  Angiotensin II type 2 receptor- and acetylcholine-mediated relaxation: essential contribution of female sex hormones and chromosomes. , 2015, Hypertension.

[78]  Jeannie T. Lee,et al.  Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation. , 2015, Science.

[79]  N. Brockdorff,et al.  A Pooled shRNA Screen Identifies Rbm15, Spen, and Wtap as Factors Required for Xist RNA-Mediated Silencing , 2015, Cell reports.

[80]  S. Thore,et al.  Identification of Spen as a Crucial Factor for Xist Function through Forward Genetic Screening in Haploid Embryonic Stem Cells , 2015, Cell reports.

[81]  A. Plutynski,et al.  An integrative view on sex differences in brain tumors , 2015, Cellular and Molecular Life Sciences.

[82]  Dmitri D. Pervouchine,et al.  The human transcriptome across tissues and individuals , 2015, Science.

[83]  Qiangfeng Cliff Zhang,et al.  Systematic Discovery of Xist RNA Binding Proteins , 2015, Cell.

[84]  Michael J. Sweredoski,et al.  The Xist lncRNA directly interacts with SHARP to silence transcription through HDAC3 , 2015, Nature.

[85]  William Stafford Noble,et al.  The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation , 2015, Genome Biology.

[86]  William Stafford Noble,et al.  Escape from X Inactivation Varies in Mouse Tissues , 2015, PLoS genetics.

[87]  J. Gécz,et al.  Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity. , 2015, Human molecular genetics.

[88]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[89]  Carolyn J. Brown,et al.  Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation , 2014, Human molecular genetics.

[90]  N. Horowitz,et al.  Does Gender Matter in Non-Hodgkin Lymphoma? Differences in Epidemiology, Clinical Behavior, and Therapy , 2014, Rambam Maimonides medical journal.

[91]  C. Disteche,et al.  X chromosome regulation: diverse patterns in development, tissues and disease , 2014, Nature Reviews Genetics.

[92]  Fang Fang,et al.  The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. , 2014, Blood.

[93]  David R. Kelley,et al.  Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre , 2014, Nature Structural &Molecular Biology.

[94]  L. Carrel,et al.  Deletion of an X-Inactivation Boundary Disrupts Adjacent Gene Silencing , 2013, PLoS genetics.

[95]  Carolyn J. Brown,et al.  Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome , 2013, Genome Biology.

[96]  Jeannie T. Lee,et al.  Guided by RNAs: X-inactivation as a model for lncRNA function. , 2013, Journal of molecular biology.

[97]  Wei Sun,et al.  Site-Specific Silencing of Regulatory Elements as a Mechanism of X Inactivation , 2012, Cell.

[98]  C. Disteche.  Dosage compensation of the sex chromosomes. , 2012, Annual review of genetics.

[99]  B. Chadwick,et al.  The macrosatellite DXZ4 mediates CTCF-dependent long-range intrachromosomal interactions on the human inactive X chromosome. , 2012, Human molecular genetics.

[100]  T. Magnuson,et al.  The mouse DXZ4 homolog retains Ctcf binding and proximity to Pls3 despite substantial organizational differences compared to the primate macrosatellite , 2012, Genome Biology.

[101]  G. Montana,et al.  Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome , 2012, Developmental cell.

[102]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

[103]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[104]  L. Liang,et al.  Enigmatic sex disparities in cancer incidence , 2012, European Journal of Epidemiology.

[105]  W. V. van IJcken,et al.  The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA. , 2011, Genes & development.

[106]  C. Disteche,et al.  Genes that escape from X inactivation , 2011, Human Genetics.

[107]  Robert W. Williams,et al.  Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse , 2010, BMC Genomics.

[108]  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.

[109]  E. Heard,et al.  Dynamic changes in paternal X-chromosome activity during imprinted X-chromosome inactivation in mice , 2009, Proceedings of the National Academy of Sciences.

[110]  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.

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

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

[113]  C. Disteche,et al.  Sex-Specific Differences in Expression of Histone Demethylases Utx and Uty in Mouse Brain and Neurons , 2008, The Journal of Neuroscience.

[114]  J. Ward,et al.  Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. , 2007, Immunity.

[115]  E. Heard,et al.  The ins and outs of gene regulation and chromosome territory organisation. , 2007, Current opinion in cell biology.

[116]  Jeannie T. Lee,et al.  Perinucleolar Targeting of the Inactive X during S Phase: Evidence for a Role in the Maintenance of Silencing , 2007, Cell.

[117]  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.

[118]  J. Mcneil,et al.  The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences , 2006, Proceedings of the National Academy of Sciences of the United States of America.

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

[120]  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.

[121]  R. Gelber,et al.  Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[123]  C. Costanzi,et al.  Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals , 1998, Nature.

[124]  C Cremer,et al.  Differences of size and shape of active and inactive X‐chromosome domains in human amniotic fluid cell nuclei , 1993, Microscopy research and technique.

[125]  G. Spindler,et al.  An Integrative View , 1992 .

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

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

[128]  Carolyn J. Brown,et al.  Localization of the X inactivation centre on the human X chromosome in Xq13 , 1991, Nature.

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

[130]  J. Graves.  Evolution of vertebrate sex chromosomes and dosage compensation. , 2016, Nature reviews. Genetics.

[131]  Yi Feng,et al.  Long Non-Coding RNAs , 2016, Methods in Molecular Biology.

[132]  Konstantinos J. Mavrakis,et al.  The H 3 K 27 me 3 demethylase UTX is a gender-speci fi c tumor suppressor in T-cell acute lymphoblastic leukemia , 2014 .

[133]  I. Amit,et al.  Comprehensive mapping of long-range interactions reveals folding principles of the human genome. , 2009, Science.

[134]  B. van Steensel,et al.  Chromatin domains in higher eukaryotes: insights from genome-wide mapping studies , 2009, Chromosoma.

[135]  D. Weisenburger,et al.  Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. , 2006, Blood.

[136]  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.

[137]  E. Heard,et al.  Mammalian X-chromosome inactivation: an epigenetics paradigm. , 2004, Cold Spring Harbor symposia on quantitative biology.

[138]  M. A. Goldman,et al.  Mammalian X chromosome inactivation. , 1992, Molecular genetic medicine.