Replication Domains: Genome Compartmentalization into Functional Replication Units

  • Peiyao A. Zhao
  • Juan Carlos Rivera-Mulia
  • David M. GilbertEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1042)


DNA replication occurs in a defined temporal order during S phase, known as the replication timing programme, which is regulated not only during the cell cycle but also during the process of development and differentiation. The units of replication timing regulation, known as replication domains (RDs), frequently comprise several nearly synchronously firing replication origins. Replication domains correspond to topologically associating domains (TADs) mapped by chromatin conformation capture methods and are likely to be the molecular equivalents of replication foci observed using cytogenetic methods. Both TAD and replication foci are considered to be stable structural units of chromosomes, conserved through the cell cycle and development, and accordingly, the boundaries of RDs also appear to be stable in different cell types. During both normal development and progression of disease, distinct cell states are characterized by unique replication timing signatures, with approximately half of genomic RDs switching replication timing between these cell states. Advances in functional genomics provide hope that we can soon gain an understanding of the cause and consequence of the replication timing programme and its myriad correlations with chromatin context and gene regulation.


Replication timing (RT) Replication foci Replication domain (RD) Topologically associating domain (TAD) Chromatin Nucleus Cell cycle 


  1. Akhtar W, de Jong J, Pindyurin AV, Pagie L, Meuleman W, de Ridder J, Berns A, Wessels LF, van Lohuizen M, van Steensel B (2013) Chromatin position effects assayed by thousands of reporters integrated in parallel. Cell 154:914–927PubMedCrossRefGoogle Scholar
  2. Alabert C, Groth A (2012) Chromatin replication and epigenome maintenance. Nat Rev Mol Cell Biol 13:153–167PubMedCrossRefGoogle Scholar
  3. Alabert C, Barth TK, Reveron-Gomez N, Sidoli S, Schmidt A, Jensen ON, Imhof A, Groth A (2015) Two distinct modes for propagation of histone PTMs across the cell cycle. Genes Dev 29:585–590PubMedPubMedCentralCrossRefGoogle Scholar
  4. Amendola M, van Steensel B (2014) Mechanisms and dynamics of nuclear lamina-genome interactions. Curr Opin Cell Biol 28:61–68PubMedCrossRefGoogle Scholar
  5. Amiel A, Kolodizner T, Fishman A, Gaber E, Klein Z, Beyth Y, Fejgin MD (1998a) Replication pattern of the p53 and 21q22 loci in the premalignant and malignant stages of carcinoma of the cervix. Cancer 83:1966–1971PubMedCrossRefGoogle Scholar
  6. Amiel A, Litmanovitch T, Lishner M, Mor A, Gaber E, Tangi I, Fejgin M, Avivi L (1998b) Temporal differences in replication timing of homologous loci in malignant cells derived from CML and lymphoma patients. Genes Chromosom Cancer 22:225–231PubMedCrossRefGoogle Scholar
  7. Amiel A, Kirgner I, Gaber E, Manor Y, Fejgin M, Lishner M (1999) Replication pattern in cancer: asynchronous replication in multiple myeloma and in monoclonal gammopathy. Cancer Genet Cytogenet 108:32–37PubMedCrossRefGoogle Scholar
  8. Avner P, Heard E (2001) X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet 2:59–67PubMedCrossRefGoogle Scholar
  9. Azmi IF, Watanabe S, Maloney MF, Kang S, Belsky JA, MacAlpine DM, Peterson CL, Bell SP (2017) Nucleosomes influence multiple steps during replication initiation. Elife 6Google Scholar
  10. Baddeley D, Chagin VO, Schermelleh L, Martin S, Pombo A, Carlton PM, Gahl A, Domaing P, Birk U, Leonhardt H et al (2010) Measurement of replication structures at the nanometer scale using super-resolution light microscopy. Nucleic Acids Res 38:–e8Google Scholar
  11. Baer D (1965) Asynchronous replication of DNA in a heterochromatic set of chromosomes in Pseudococcus obscurus. Genetics 52:275–285PubMedPubMedCentralGoogle Scholar
  12. Bellelli R, Castellone MD, Guida T, Limongello R, Dathan NA, Merolla F, Cirafici AM, Affuso A, Masai H, Costanzo V et al (2014) NCOA4 transcriptional coactivator inhibits activation of DNA replication origins. Mol Cell 55:123–137PubMedCrossRefGoogle Scholar
  13. Belotserkovskaya R, Oh S, Bondarenko VA, Orphanides G, Studitsky VM, Reinberg D (2003) FACT facilitates transcription-dependent nucleosome alteration. Science 301:1090–1093PubMedCrossRefGoogle Scholar
  14. Bender W, Fitzgerald DP (2002) Transcription activates repressed domains in the Drosophila bithorax complex. Development 129:4923–4930PubMedGoogle Scholar
  15. Berezney R, Dubey DD, Huberman JA (2000) Heterogeneity of eukaryotic replicons, replicon clusters, and replication foci. Chromosoma 108:471–484PubMedCrossRefGoogle Scholar
  16. Besnard E, Babled A, Lapasset L, Milhavet O, Parrinello H, Dantec C, Marin JM, Lemaitre JM (2012) Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs. Nat Struct Mol Biol 19:837–844PubMedCrossRefGoogle Scholar
  17. Blow JJ, Dutta A (2005) Preventing re-replication of chromosomal DNA. Nat Rev Mol Cell Biol 6:476–486PubMedPubMedCentralCrossRefGoogle Scholar
  18. Breger KS, Smith L, Turker MS, Thayer MJ (2004) Ionizing radiation induces frequent translocations with delayed replication and condensation. Cancer Res 64:8231–8238PubMedCrossRefGoogle Scholar
  19. Breger KS, Smith L, Thayer MJ (2005) Engineering translocations with delayed replication: evidence for cis control of chromosome replication timing. Hum Mol Genet 14:2813–2827PubMedCrossRefGoogle Scholar
  20. Casas-Delucchi CS, Brero A, Rahn HP, Solovei I, Wutz A, Cremer T, Leonhardt H, Cardoso MC (2011) Histone acetylation controls the inactive X chromosome replication dynamics. Nat Commun 2:222PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cavalli G, Misteli T (2013) Functional implications of genome topology. Nat Struct Mol Biol 20:290–299PubMedCrossRefGoogle Scholar
  22. Cayrou C, Coulombe P, Vigneron A, Stanojcic S, Ganier O, Peiffer I, Rivals E, Puy A, Laurent-Chabalier S, Desprat R et al (2011) Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features. Genome Res 21:1438–1449PubMedPubMedCentralCrossRefGoogle Scholar
  23. Cayrou C, Coulombe P, Puy A, Rialle S, Kaplan N, Segal E, Mechali M (2012) New insights into replication origin characteristics in metazoans. Cell Cycle 11:658–667PubMedPubMedCentralCrossRefGoogle Scholar
  24. Cayrou C, Ballester B, Peiffer I, Fenouil R, Coulombe P, Andrau JC, van Helden J, Mechali M (2015) The chromatin environment shapes DNA replication origin organization and defines origin classes. Genome Res 25:1873–1885PubMedPubMedCentralCrossRefGoogle Scholar
  25. Chagin VO, Casas-Delucchi CS, Reinhart M, Schermelleh L, Markaki Y, Maiser A, Bolius JJ, Bensimon A, Fillies M, Domaing P et al (2016) 4D visualization of replication foci in mammalian cells corresponding to individual replicons. Nat Commun 7:11231PubMedPubMedCentralCrossRefGoogle Scholar
  26. Chakalova L, Debrand E, Mitchell JA, Osborne CS, Fraser P (2005) Replication and transcription: shaping the landscape of the genome. Nat Rev Genet 6:669–677PubMedCrossRefGoogle Scholar
  27. Chang BH, Smith L, Huang J, Thayer M (2007) Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability. Oncogene 26:1852–1861PubMedCrossRefGoogle Scholar
  28. Cornacchia D, Dileep V, Quivy JP, Foti R, Tili F, Santarella-Mellwig R, Antony C, Almouzni G, Gilbert DM, Buonomo SB (2012) Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells. EMBO J 31:3678–3690PubMedPubMedCentralCrossRefGoogle Scholar
  29. Costantini M, Bernardi G (2008) Replication timing, chromosomal bands, and isochores. Proc Natl Acad Sci U S A 105:3433–3437PubMedPubMedCentralCrossRefGoogle Scholar
  30. Costantini M, Clay O, Federico C, Saccone S, Auletta F, Bernardi G (2007) Human chromosomal bands: nested structure, high-definition map and molecular basis. Chromosoma 116:29–40PubMedCrossRefGoogle Scholar
  31. Cremer T, Cremer M (2010) Chromosome territories. Cold Spring Harb Perspect Biol 2:a003889PubMedPubMedCentralCrossRefGoogle Scholar
  32. Cremer T, Cremer M, Dietzel S, Muller S, Solovei I, Fakan S (2006) Chromosome territories – a functional nuclear landscape. Curr Opin Cell Biol 18:307–316PubMedCrossRefGoogle Scholar
  33. Deegan TD, Diffley JF (2016) MCM: one ring to rule them all. Curr Opin Struct Biol 37:145–151PubMedCrossRefGoogle Scholar
  34. Demczuk A, Gauthier MG, Veras I, Kosiyatrakul S, Schildkraut CL, Busslinger M, Bechhoefer J, Norio P (2012) Regulation of DNA replication within the immunoglobulin heavy-chain locus during B cell commitment. PLoS Biol 10:e1001360PubMedPubMedCentralCrossRefGoogle Scholar
  35. Deng X, Zhironkina OA, Cherepanynets VD, Strelkova OS, Kireev II, Belmont AS (2016) Cytology of DNA replication reveals dynamic plasticity of large-scale chromatin fibers. Curr Biol 26:2527–2534PubMedPubMedCentralCrossRefGoogle Scholar
  36. Dileep V, Rivera-Mulia JC, Sima J, Gilbert DM (2015a) Large-scale chromatin structure-function relationships during the cell cycle and development: insights from replication timing. Cold Spring Harb Symp Quant Biol 80:53–63PubMedCrossRefGoogle Scholar
  37. Dileep V, Ay F, Sima J, Vera DL, Noble WS, Gilbert DM (2015b) Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program. Genome Res 25:1104–1113PubMedPubMedCentralCrossRefGoogle Scholar
  38. Dimitrova DS, Gilbert DM (1999) The spatial position and replication timing of chromosomal domains are both established in early G1 phase. Mol Cell 4:983–993PubMedCrossRefGoogle Scholar
  39. Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380PubMedPubMedCentralCrossRefGoogle Scholar
  40. Donley N, Thayer MJ (2013) DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability. Semin Cancer Biol 23:80–89PubMedPubMedCentralCrossRefGoogle Scholar
  41. Donzelli M, Draetta GF (2003) Regulating mammalian checkpoints through Cdc25 inactivation. EMBO Rep 4:671–677PubMedPubMedCentralCrossRefGoogle Scholar
  42. Elgin SC, Reuter G (2013) Position-effect variegation, heterochromatin formation, and gene silencing in drosophila. Cold Spring Harb Perspect Biol 5:a017780PubMedPubMedCentralCrossRefGoogle Scholar
  43. Ermakova OV, Nguyen LH, Little RD, Chevillard C, Riblet R, Ashouian N, Birshtein BK, Schildkraut CL (1999) Evidence that a single replication fork proceeds from early to late replicating domains in the IgH locus in a non-B cell line. Mol Cell 3:321–330PubMedCrossRefGoogle Scholar
  44. Farago M, Rosenbluh C, Tevlin M, Fraenkel S, Schlesinger S, Masika H, Gouzman M, Teng G, Schatz D, Rais Y et al (2012) Clonal allelic predetermination of immunoglobulin-kappa rearrangement. Nature 490:561–565PubMedCrossRefGoogle Scholar
  45. Feng Y, Vlassis A, Roques C, Lalonde ME, Gonzalez-Aguilera C, Lambert JP, Lee SB, Zhao X, Alabert C, Johansen JV et al (2016) BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation. EMBO J 35:176–192PubMedCrossRefGoogle Scholar
  46. Ferguson BM, Brewer BJ, Reynolds AE, Fangman WL (1991) A yeast origin of replication is activated late in S phase. Cell 65:507–515PubMedCrossRefGoogle Scholar
  47. Ferreira J, Paolella G, Ramos C, Lamond AI (1997) Spatial organization of large-scale chromatin domains in the nucleus: a magnified view of single chromosome territories. J Cell Biol 139:1597–1610PubMedPubMedCentralCrossRefGoogle Scholar
  48. Foti R, Gnan S, Cornacchia D, Dileep V, Bulut-Karslioglu A, Diehl S, Buness A, Klein FA, Huber W, Johnstone E et al (2016) Nuclear architecture organized by Rif1 underpins the replication-timing program. Mol Cell 61:260–273PubMedPubMedCentralCrossRefGoogle Scholar
  49. Foulk MS, Urban JM, Casella C, Gerbi SA (2015) Characterizing and controlling intrinsic biases of lambda exonuclease in nascent strand sequencing reveals phasing between nucleosomes and G-quadruplex motifs around a subset of human replication origins. Genome Res 25:725–735PubMedPubMedCentralCrossRefGoogle Scholar
  50. Fragkos M, Ganier O, Coulombe P, Mechali M (2015) DNA replication origin activation in space and time. Nat Rev Mol Cell Biol 16:360–374PubMedCrossRefGoogle Scholar
  51. Ge XQ, Blow JJ (2010) Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories. J Cell Biol 191:1285–1297PubMedPubMedCentralCrossRefGoogle Scholar
  52. Gifford CA, Ziller MJ, Gu H, Trapnell C, Donaghey J, Tsankov A, Shalek AK, Kelley DR, Shishkin AA, Issner R et al (2013) Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell 153:1149–1163PubMedPubMedCentralCrossRefGoogle Scholar
  53. Gilbert DM (1986) Temporal order of replication of Xenopus laevis 5S ribosomal RNA genes in somatic cells. Proc Natl Acad Sci U S A 83:2924–2928PubMedPubMedCentralCrossRefGoogle Scholar
  54. Gilbert DM (2002) Replication timing and metazoan evolution. Nat Genet 32:336–337PubMedCrossRefGoogle Scholar
  55. Gilbert DM (2010) Evaluating genome-scale approaches to eukaryotic DNA replication. Nat Rev Genet 11:673–684PubMedPubMedCentralCrossRefGoogle Scholar
  56. Gilbert DM, Cohen SN (1987) Bovine papilloma virus plasmids replicate randomly in mouse fibroblasts throughout S phase of the cell cycle. Cell 50:59–68PubMedCrossRefGoogle Scholar
  57. Gilbert DM, Cohen SN (1990) Position effects on the timing of replication of chromosomally integrated simian virus 40 molecules in Chinese hamster cells. Mol Cell Biol 10:4345–4355PubMedPubMedCentralCrossRefGoogle Scholar
  58. Gindin Y, Valenzuela MS, Aladjem MI, Meltzer PS, Bilke S (2014) A chromatin structure-based model accurately predicts DNA replication timing in human cells. Mol Syst Biol 10:722PubMedPubMedCentralCrossRefGoogle Scholar
  59. Goldar A, Labit H, Marheineke K, Hyrien O (2008) A dynamic stochastic model for DNA replication initiation in early embryos. PLoS One 3:e2919PubMedPubMedCentralCrossRefGoogle Scholar
  60. Goldar A, Arneodo A, Audit B, Argoul F, Rappailles A, Guilbaud G, Petryk N, Kahli M, Hyrien O (2016) Deciphering DNA replication dynamics in eukaryotic cell populations in relation with their averaged chromatin conformations. Sci Rep 6:22469PubMedPubMedCentralCrossRefGoogle Scholar
  61. Goldman MA, Holmquist GP, Gray MC, Caston LA, Nag A (1984) Replication timing of genes and middle repetitive sequences. Science 224:686–692PubMedCrossRefGoogle Scholar
  62. Goren A, Tabib A, Hecht M, Cedar H (2008) DNA replication timing of the human beta-globin domain is controlled by histone modification at the origin. Genes Dev 22:1319–1324PubMedPubMedCentralCrossRefGoogle Scholar
  63. Guillou E, Ibarra A, Coulon V, Casado-Vela J, Rico D, Casal I, Schwob E, Losada A, Mendez J (2010) Cohesin organizes chromatin loops at DNA replication factories. Genes Dev 24:2812–2822PubMedPubMedCentralCrossRefGoogle Scholar
  64. Guinta DR, Korn LJ (1986) Differential order of replication of Xenopus laevis 5S RNA genes. Mol Cell Biol 6:2536–2542PubMedPubMedCentralCrossRefGoogle Scholar
  65. Hansen RS, Canfield TK, Lamb MM, Gartler SM, Laird CD (1993) Association of fragile X syndrome with delayed replication of the FMR1 gene. Cell 73:1403–1409PubMedCrossRefGoogle Scholar
  66. Hansen RS, Stoger R, Wijmenga C, Stanek AM, Canfield TK, Luo P, Matarazzo MR, D'Esposito M, Feil R, Gimelli G et al (2000) Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant. Hum Mol Genet 9:2575–2587PubMedCrossRefGoogle Scholar
  67. Hatton KS, Dhar V, Brown EH, Iqbal MA, Stuart S, Didamo VT, Schildkraut CL (1988) Replication program of active and inactive multigene families in mammalian cells. Mol Cell Biol 8:2149–2158PubMedPubMedCentralCrossRefGoogle Scholar
  68. Himes M (1967) An analysis of heterochromatin in maize root tips. J Cell Biol 35:175–181PubMedPubMedCentralCrossRefGoogle Scholar
  69. Hiratani I, Leskovar A, Gilbert DM (2004) Differentiation-induced replication-timing changes are restricted to AT-rich/long interspersed nuclear element (LINE)-rich isochores. Proc Natl Acad Sci U S A 101:16861–16866PubMedPubMedCentralCrossRefGoogle Scholar
  70. Hiratani I, Ryba T, Itoh M, Yokochi T, Schwaiger M, Chang CW, Lyou Y, Townes TM, Schubeler D, Gilbert DM (2008) Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol 6:e245PubMedPubMedCentralCrossRefGoogle Scholar
  71. Hiratani I, Takebayashi S, Lu J, Gilbert DM (2009) Replication timing and transcriptional control: beyond cause and effect – part II. Curr Opin Genet Dev 19:142–149PubMedPubMedCentralCrossRefGoogle Scholar
  72. Hiratani I, Ryba T, Itoh M, Rathjen J, Kulik M, Papp B, Fussner E, Bazett-Jones DP, Plath K, Dalton S et al (2010) Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis. Genome Res 20:155–169PubMedPubMedCentralCrossRefGoogle Scholar
  73. Hogga I, Karch F (2002) Transcription through the iab-7 cis-regulatory domain of the bithorax complex interferes with maintenance of Polycomb-mediated silencing. Development 129:4915–4922PubMedGoogle Scholar
  74. Holmquist GP (1987) Role of replication time in the control of tissue-specific gene expression. Am J Hum Genet 40:151–173PubMedPubMedCentralGoogle Scholar
  75. Hozak P, Hassan AB, Jackson DA, Cook PR (1993) Visualization of replication factories attached to nucleoskeleton. Cell 73:361–373PubMedCrossRefGoogle Scholar
  76. Huang H, Stromme CB, Saredi G, Hodl M, Strandsby A, Gonzalez-Aguilera C, Chen S, Groth A, Patel DJ (2015) A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks. Nat Struct Mol Biol 22:618–626PubMedPubMedCentralCrossRefGoogle Scholar
  77. Hyrien O (2015) Peaks cloaked in the mist: the landscape of mammalian replication origins. J Cell Biol 208:147–160PubMedPubMedCentralCrossRefGoogle Scholar
  78. Jackson DA, Pombo A (1998) Replicon clusters are stable units of chromosome structure: evidence that nuclear organization contributes to the efficient activation and propagation of S phase in human cells. J Cell Biol 140:1285–1295PubMedPubMedCentralCrossRefGoogle Scholar
  79. Karnani N, Taylor CM, Malhotra A, Dutta A (2010) Genomic study of replication initiation in human chromosomes reveals the influence of transcription regulation and chromatin structure on origin selection. Mol Biol Cell 21:393–404PubMedPubMedCentralCrossRefGoogle Scholar
  80. Kaykov A, Nurse P (2015) The spatial and temporal organization of origin firing during the S-phase of fission yeast. Genome Res 25:391–401PubMedPubMedCentralCrossRefGoogle Scholar
  81. Keohane AM, O’Neill LP, Belyaev ND, Lavender JS, Turner BM (1996) X-inactivation and histone H4 acetylation in embryonic stem cells. Dev Biol 180:618–630PubMedCrossRefGoogle Scholar
  82. Kireeva ML, Walter W, Tchernajenko V, Bondarenko V, Kashlev M, Studitsky VM (2002) Nucleosome remodeling induced by RNA polymerase II: loss of the H2A/H2B dimer during transcription. Mol Cell 9:541–552PubMedCrossRefGoogle Scholar
  83. Kitamura E, Blow JJ, Tanaka TU (2006) Live-cell imaging reveals replication of individual replicons in eukaryotic replication factories. Cell 125:1297–1308PubMedPubMedCentralCrossRefGoogle Scholar
  84. Kitsberg D, Selig S, Brandeis M, Simon I, Keshet I, Driscoll DJ, Nicholls RD, Cedar H (1993) Allele-specific replication timing of imprinted gene regions. Nature 364:459–463PubMedCrossRefGoogle Scholar
  85. Klevecz RR, Stubblefield E (1967) RNA synthesis in relation to DNA replication in synchronized Chinese hamster cell cultures. J Exp Zool 165:259–268PubMedCrossRefGoogle Scholar
  86. Knott SR, Peace JM, Ostrow AZ, Gan Y, Rex AE, Viggiani CJ, Tavare S, Aparicio OM (2012) Forkhead transcription factors establish origin timing and long-range clustering in S. cerevisiae. Cell 148:99–111PubMedPubMedCentralCrossRefGoogle Scholar
  87. Koren A, Polak P, Nemesh J, Michaelson JJ, Sebat J, Sunyaev SR, McCarroll SA (2012) Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet 91:1033–1040PubMedPubMedCentralCrossRefGoogle Scholar
  88. Koren A, Handsaker RE, Kamitaki N, Karlic R, Ghosh S, Polak P, Eggan K, McCarroll SA (2014) Genetic variation in human DNA replication timing. Cell 159:1015–1026PubMedPubMedCentralCrossRefGoogle Scholar
  89. Korenstein-Ilan A, Amiel A, Lalezari S, Lishner M, Avivi L (2002) Allele-specific replication associated with aneuploidy in blood cells of patients with hematologic malignancies. Cancer Genet Cytogenet 139:97–103PubMedCrossRefGoogle Scholar
  90. Kosak ST, Skok JA, Medina KL, Riblet R, Le Beau MM, Fisher AG, Singh H (2002) Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296:158–162PubMedCrossRefGoogle Scholar
  91. Kylie K, Romero J, Lindamulage IK, Knockleby J, Lee H (2016) Dynamic regulation of histone H3K9 is linked to the switch between replication and transcription at the Dbf4 origin-promoter locus. Cell Cycle 15:2321–2335PubMedPubMedCentralCrossRefGoogle Scholar
  92. Lande-Diner L, Zhang J, Cedar H (2009) Shifts in replication timing actively affect histone acetylation during nucleosome reassembly. Mol Cell 34:767–774PubMedPubMedCentralCrossRefGoogle Scholar
  93. Lang GI, Murray AW (2011) Mutation rates across budding yeast chromosome VI are correlated with replication timing. Genome Biol Evol 3:799–811PubMedPubMedCentralCrossRefGoogle Scholar
  94. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:289–293PubMedPubMedCentralCrossRefGoogle Scholar
  95. Lima-De-Faria A (1959) Differential uptake of tritiated thymidine into hetero- and euchromatin in Melanoplus and Secale. J Biophys Biochem Cytol 6:457–466PubMedPubMedCentralCrossRefGoogle Scholar
  96. Liu S, Trapnell C (2016) Single-cell transcriptome sequencing: recent advances and remaining challenges. F1000Res 5Google Scholar
  97. Liu J, McConnell K, Dixon M, Calvi BR (2012) Analysis of model replication origins in Drosophila reveals new aspects of the chromatin landscape and its relationship to origin activity and the prereplicative complex. Mol Biol Cell 23:200–212PubMedPubMedCentralCrossRefGoogle Scholar
  98. Liu L, De S, Michor F (2013) DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Nat Commun 4:1502PubMedPubMedCentralCrossRefGoogle Scholar
  99. Lob D, Lengert N, Chagin VO, Reinhart M, Casas-Delucchi CS, Cardoso MC, Drossel B (2016) 3D replicon distributions arise from stochastic initiation and domino-like DNA replication progression. Nat Commun 7:11207PubMedPubMedCentralCrossRefGoogle Scholar
  100. Lu J, Li F, Murphy CS, Davidson MW, Gilbert DM (2010) G2 phase chromatin lacks determinants of replication timing. J Cell Biol 189:967–980PubMedPubMedCentralCrossRefGoogle Scholar
  101. Lubelsky Y, Prinz JA, DeNapoli L, Li Y, Belsky JA, MacAlpine DM (2014) DNA replication and transcription programs respond to the same chromatin cues. Genome Res 24:1102–1114PubMedPubMedCentralCrossRefGoogle Scholar
  102. Ma H, Samarabandu J, Devdhar RS, Acharya R, Cheng PC, Meng C, Berezney R (1998) Spatial and temporal dynamics of DNA replication sites in mammalian cells. J Cell Biol 143:1415–1425PubMedPubMedCentralCrossRefGoogle Scholar
  103. Maya-Mendoza A, Olivares-Chauvet P, Shaw A, Jackson DA (2010) S phase progression in human cells is dictated by the genetic continuity of DNA foci. PLoS Genet 6:e1000900PubMedPubMedCentralCrossRefGoogle Scholar
  104. Maya-Mendoza A, Olivares-Chauvet P, Kohlmeier F, Jackson DA (2012) Visualising chromosomal replication sites and replicons in mammalian cells. Methods 57:140–148PubMedCrossRefGoogle Scholar
  105. Meister P, Taddei A, Ponti A, Baldacci G, Gasser SM (2007) Replication foci dynamics: replication patterns are modulated by S-phase checkpoint kinases in fission yeast. EMBO J 26:1315–1326PubMedPubMedCentralCrossRefGoogle Scholar
  106. Mesner LD, Valsakumar V, Cieslik M, Pickin R, Hamlin JL, Bekiranov S (2013) Bubble-seq analysis of the human genome reveals distinct chromatin-mediated mechanisms for regulating early- and late-firing origins. Genome Res 23:1774–1788PubMedPubMedCentralCrossRefGoogle Scholar
  107. Meuleman W, Peric-Hupkes D, Kind J, Beaudry JB, Pagie L, Kellis M, Reinders M, Wessels L, van Steensel B (2013) Constitutive nuclear lamina-genome interactions are highly conserved and associated with A/T-rich sequence. Genome Res 23:270–280PubMedPubMedCentralCrossRefGoogle Scholar
  108. Moindrot B, Audit B, Klous P, Baker A, Thermes C, de Laat W, Bouvet P, Mongelard F, Arneodo A (2012) 3D chromatin conformation correlates with replication timing and is conserved in resting cells. Nucleic Acids Res 40:9470–9481PubMedPubMedCentralCrossRefGoogle Scholar
  109. Mostoslavsky R, Singh N, Tenzen T, Goldmit M, Gabay C, Elizur S, Qi P, Reubinoff BE, Chess A, Cedar H et al (2001) Asynchronous replication and allelic exclusion in the immune system. Nature 414:221–225PubMedCrossRefGoogle Scholar
  110. Nakamura H, Morita T, Sato C (1986) Structural organizations of replicon domains during DNA synthetic phase in the mammalian nucleus. Exp Cell Res 165:291–297PubMedCrossRefGoogle Scholar
  111. Nakayasu H, Berezney R (1989) Mapping replicational sites in the eucaryotic cell nucleus. J Cell Biol 108:1–11PubMedCrossRefGoogle Scholar
  112. Naumova N, Imakaev M, Fudenberg G, Zhan Y, Lajoie BR, Mirny LA, Dekker J (2013) Organization of the mitotic chromosome. Science 342:948–953PubMedPubMedCentralCrossRefGoogle Scholar
  113. Newlon CS, Lipchitz LR, Collins I, Deshpande A, Devenish RJ, Green RP, Klein HL, Palzkill TG, Ren RB, Synn S et al (1991) Analysis of a circular derivative of Saccharomyces cerevisiae chromosome III: a physical map and identification and location of ARS elements. Genetics 129:343–357PubMedPubMedCentralGoogle Scholar
  114. Norio P, Kosiyatrakul S, Yang Q, Guan Z, Brown NM, Thomas S, Riblet R, Schildkraut CL (2005) Progressive activation of DNA replication initiation in large domains of the immunoglobulin heavy chain locus during B cell development. Mol Cell 20:575–587PubMedCrossRefGoogle Scholar
  115. Ostrow AZ, Kalhor R, Gan Y, Villwock SK, Linke C, Barberis M, Chen L, Aparicio OM (2017) Conserved forkhead dimerization motif controls DNA replication timing and spatial organization of chromosomes in S. cerevisiae. Proc Natl Acad Sci U S A 114:E2411–E2419PubMedPubMedCentralCrossRefGoogle Scholar
  116. Patel PK, Arcangioli B, Baker SP, Bensimon A, Rhind N (2006) DNA replication origins fire stochastically in fission yeast. Mol Biol Cell 17:308–316PubMedPubMedCentralCrossRefGoogle Scholar
  117. Peric-Hupkes D, Meuleman W, Pagie L, Bruggeman SW, Solovei I, Brugman W, Graf S, Flicek P, Kerkhoven RM, van Lohuizen M et al (2010) Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol Cell 38:603–613PubMedCrossRefGoogle Scholar
  118. Perry P, Sauer S, Billon N, Richardson WD, Spivakov M, Warnes G, Livesey FJ, Merkenschlager M, Fisher AG, Azuara V (2004) A dynamic switch in the replication timing of key regulator genes in embryonic stem cells upon neural induction. Cell Cycle 3:1645–1650PubMedCrossRefGoogle Scholar
  119. Petryk N, Kahli M, d’Aubenton-Carafa Y, Jaszczyszyn Y, Shen Y, Silvain M, Thermes C, Chen CL, Hyrien O (2016) Replication landscape of the human genome. Nat Commun 7:10208PubMedPubMedCentralCrossRefGoogle Scholar
  120. Pfeiffer SE (1968) RNA synthesis in synchronously growing populations of HeLa S3 cells. II. Rate of synthesis of individual RNA fractions. J Cell Physiol 71:95–104PubMedCrossRefGoogle Scholar
  121. Pombo A, Dillon N (2015) Three-dimensional genome architecture: players and mechanisms. Nat Rev Mol Cell Biol 16:245–257PubMedCrossRefGoogle Scholar
  122. Pope BD, Tsumagari K, Battaglia D, Ryba T, Hiratani I, Ehrlich M, Gilbert DM (2011) DNA replication timing is maintained genome-wide in primary human myoblasts independent of D4Z4 contraction in FSH muscular dystrophy. PLoS One 6:e27413PubMedPubMedCentralCrossRefGoogle Scholar
  123. Pope BD, Chandra T, Buckley Q, Hoare M, Ryba T, Wiseman FK, Kuta A, Wilson MD, Odom DT, Gilbert DM (2012) Replication-timing boundaries facilitate cell-type and species-specific regulation of a rearranged human chromosome in mouse. Hum Mol Genet 21:4162–4170PubMedPubMedCentralCrossRefGoogle Scholar
  124. Pope BD, Ryba T, Dileep V, Yue F, Wu W, Denas O, Vera DL, Wang Y, Hansen RS, Canfield TK et al (2014) Topologically associating domains are stable units of replication-timing regulation. Nature 515:402–405PubMedPubMedCentralCrossRefGoogle Scholar
  125. Pourkarimi E, Bellush JM, Whitehouse I (2016) Spatiotemporal coupling and decoupling of gene transcription with DNA replication origins during embryogenesis in C. elegans. Elife 5:e21728PubMedPubMedCentralCrossRefGoogle Scholar
  126. Prioleau MN (2009) CpG islands: starting blocks for replication and transcription. PLoS Genet 5:e1000454PubMedPubMedCentralCrossRefGoogle Scholar
  127. Ramachandran S, Henikoff S (2015) Replicating nucleosomes. Sci Adv 1Google Scholar
  128. Ramani V, Deng X, Qiu R, Gunderson KL, Steemers FJ, Disteche CM, Noble WS, Duan Z, Shendure J (2017) Massively multiplex single-cell Hi-C. Nat Methods 14:263–266PubMedPubMedCentralCrossRefGoogle Scholar
  129. Rhind N, Gilbert DM (2013) DNA replication timing. Cold Spring Harb Perspect Biol 5:a010132PubMedPubMedCentralCrossRefGoogle Scholar
  130. Rhind N, Yang SC, Bechhoefer J (2010) Reconciling stochastic origin firing with defined replication timing. Chromosom Res 18:35–43CrossRefGoogle Scholar
  131. Rivera-Mulia JC, Gilbert DM (2016a) Replicating large genomes: divide and conquer. Mol Cell 62:756–765. PubMedPubMedCentralCrossRefGoogle Scholar
  132. Rivera-Mulia JC, Gilbert DM (2016b) Replication timing and transcriptional control: beyond cause and effect-part III. Curr Opin Cell Biol 40:168–178. PubMedPubMedCentralCrossRefGoogle Scholar
  133. Rivera-Mulia JC, Buckley Q, Sasaki T, Zimmerman J, Didier RA, Nazor K, Loring JF, Lian Z, Weissman S, Robins AJ et al (2015) Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells. Genome Res 25:1091–1103PubMedPubMedCentralCrossRefGoogle Scholar
  134. Roadmap Epigenomics C, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J et al (2015) Integrative analysis of 111 reference human epigenomes. Nature 518:317–330CrossRefGoogle Scholar
  135. Robson MI, de Las Heras JI, Czapiewski R, Le Thanh P, Booth DG, Kelly DA, Webb S, Kerr AR, Schirmer EC (2016) Tissue-specific gene repositioning by muscle nuclear membrane proteins enhances repression of critical developmental genes during myogenesis. Mol Cell 62:834–847PubMedPubMedCentralCrossRefGoogle Scholar
  136. Rondinelli B, Schwerer H, Antonini E, Gaviraghi M, Lupi A, Frenquelli M, Cittaro D, Segalla S, Lemaitre JM, Tonon G (2015) H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing. Nucleic Acids Res 43:2560–2574PubMedPubMedCentralCrossRefGoogle Scholar
  137. Ryba T, Hiratani I, Lu J, Itoh M, Kulik M, Zhang J, Schulz TC, Robins AJ, Dalton S, Gilbert DM (2010) Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res 20:761–770PubMedPubMedCentralCrossRefGoogle Scholar
  138. Ryba T, Battaglia D, Chang BH, Shirley JW, Buckley Q, Pope BD, Devidas M, Druker BJ, Gilbert DM (2012) Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia. Genome Res 22:1833–1844PubMedPubMedCentralCrossRefGoogle Scholar
  139. Sadoni N, Cardoso MC, Stelzer EH, Leonhardt H, Zink D (2004) Stable chromosomal units determine the spatial and temporal organization of DNA replication. J Cell Sci 117:5353–5365PubMedCrossRefGoogle Scholar
  140. Saner N, Karschau J, Natsume T, Gierlinski M, Retkute R, Hawkins M, Nieduszynski CA, Blow JJ, de Moura AP, Tanaka TU (2013) Stochastic association of neighboring replicons creates replication factories in budding yeast. J Cell Biol 202:1001–1012PubMedPubMedCentralCrossRefGoogle Scholar
  141. Sasaki T, Rivera-Mulia JC, Vera D, Zimmerman J, Das S, Padget M, Nakamichi N, Chang BH, Tyner J, Druker BJ, Weng AP, Civin CI, Eaves CJ, Gilbert DM (2017) Stability of patient-specific features of altered DNA replication timing in xenografts of primary human acute lymphoblastic leukemia. Exp Hematol 51:71–82.e3Google Scholar
  142. Schmitt S, Prestel M, Paro R (2005) Intergenic transcription through a polycomb group response element counteracts silencing. Genes Dev 19:697–708PubMedPubMedCentralCrossRefGoogle Scholar
  143. Schubeler D, Scalzo D, Kooperberg C, van Steensel B, Delrow J, Groudine M (2002) Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing. Nat Genet 32:438–442PubMedCrossRefGoogle Scholar
  144. Schwaiger M, Stadler MB, Bell O, Kohler H, Oakeley EJ, Schubeler D (2009) Chromatin state marks cell-type- and gender-specific replication of the Drosophila genome. Genes Dev 23:589–601PubMedPubMedCentralCrossRefGoogle Scholar
  145. Schwaiger M, Kohler H, Oakeley EJ, Stadler MB, Schubeler D (2010) Heterochromatin protein 1 (HP1) modulates replication timing of the Drosophila genome. Genome Res 20:771–780PubMedPubMedCentralCrossRefGoogle Scholar
  146. Schwartz BE, Ahmad K (2005) Transcriptional activation triggers deposition and removal of the histone variant H3.3. Genes Dev 19:804–814PubMedPubMedCentralCrossRefGoogle Scholar
  147. Sequeira-Mendes J, Diaz-Uriarte R, Apedaile A, Huntley D, Brockdorff N, Gomez M (2009) Transcription initiation activity sets replication origin efficiency in mammalian cells. PLoS Genet 5:e1000446PubMedPubMedCentralCrossRefGoogle Scholar
  148. Simon I, Tenzen T, Reubinoff BE, Hillman D, McCarrey JR, Cedar H (1999) Asynchronous replication of imprinted genes is established in the gametes and maintained during development. Nature 401:929–932PubMedCrossRefGoogle Scholar
  149. Smith L, Plug A, Thayer M (2001) Delayed replication timing leads to delayed mitotic chromosome condensation and chromosomal instability of chromosome translocations. Proc Natl Acad Sci U S A 98:13300–13305PubMedPubMedCentralCrossRefGoogle Scholar
  150. Solovei I, Thanisch K, Feodorova Y (2016) How to rule the nucleus: divide et impera. Curr Opin Cell Biol 40:47–59. PubMedCrossRefGoogle Scholar
  151. Sparvoli E, Levi M, Rossi E (1994) Replicon clusters may form structurally stable complexes of chromatin and chromosomes. J Cell Sci 107(Pt 11):3097–3103PubMedGoogle Scholar
  152. Sporbert A, Gahl A, Ankerhold R, Leonhardt H, Cardoso MC (2002) DNA polymerase clamp shows little turnover at established replication sites but sequential de novo assembly at adjacent origin clusters. Mol Cell 10:1355–1365PubMedCrossRefGoogle Scholar
  153. Stamatoyannopoulos JA, Adzhubei I, Thurman RE, Kryukov GV, Mirkin SM, Sunyaev SR (2009) Human mutation rate associated with DNA replication timing. Nat Genet 41:393–395PubMedPubMedCentralCrossRefGoogle Scholar
  154. Supek F, Lehner B (2015) Differential DNA mismatch repair underlies mutation rate variation across the human genome. Nature 521:81–84PubMedPubMedCentralCrossRefGoogle Scholar
  155. Takebayashi S, Dileep V, Ryba T, Dennis JH, Gilbert DM (2012) Chromatin-interaction compartment switch at developmentally regulated chromosomal domains reveals an unusual principle of chromatin folding. Proc Natl Acad Sci U S A 109:12574–12579PubMedPubMedCentralCrossRefGoogle Scholar
  156. Tardat M, Brustel J, Kirsh O, Lefevbre C, Callanan M, Sardet C, Julien E (2010) The histone H4 Lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells. Nat Cell Biol 12:1086–1093PubMedCrossRefGoogle Scholar
  157. Taylor JH (1960) Asynchronous duplication of chromosomes in cultured cells of Chinese hamster. J Biophys Biochem Cytol 7:455–464PubMedPubMedCentralCrossRefGoogle Scholar
  158. Therizols P, Illingworth RS, Courilleau C, Boyle S, Wood AJ, Bickmore WA (2014) Chromatin decondensation is sufficient to alter nuclear organization in embryonic stem cells. Science 346:1238–1242PubMedCrossRefGoogle Scholar
  159. Valton AL, Hassan-Zadeh V, Lema I, Boggetto N, Alberti P, Saintome C, Riou JF, Prioleau MN (2014) G4 motifs affect origin positioning and efficiency in two vertebrate replicators. EMBO J 33:732–746PubMedPubMedCentralCrossRefGoogle Scholar
  160. Vogelstein B, Pardoll DM, Coffey DS (1980) Supercoiled loops and eukaryotic DNA replication. Cell 22:79–85PubMedCrossRefGoogle Scholar
  161. Wang Y, Khan A, Marks AB, Smith OK, Giri S, Lin YC, Creager R, MacAlpine DM, Prasanth KV, Aladjem MI et al (2016) Temporal association of ORCA/LRWD1 to late-firing origins during G1 dictates heterochromatin replication and organization. Nucleic Acids Res 45:2490–2502PubMedCentralCrossRefGoogle Scholar
  162. Williams RR, Azuara V, Perry P, Sauer S, Dvorkina M, Jorgensen H, Roix J, McQueen P, Misteli T, Merkenschlager M et al (2006) Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus. J Cell Sci 119:132–140PubMedCrossRefGoogle Scholar
  163. Woodfine K, Fiegler H, Beare DM, Collins JE, McCann OT, Young BD, Debernardi S, Mott R, Dunham I, Carter NP (2004) Replication timing of the human genome. Hum Mol Genet 13:191–202PubMedCrossRefGoogle Scholar
  164. Woodward AM, Gohler T, Luciani MG, Oehlmann M, Ge X, Gartner A, Jackson DA, Blow JJ (2006) Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. J Cell Biol 173:673–683PubMedPubMedCentralCrossRefGoogle Scholar
  165. Wu R, Wang Z, Zhang H, Gan H, Zhang Z (2017) H3K9me3 demethylase Kdm4d facilitates the formation of pre-initiative complex and regulates DNA replication. Nucleic Acids Res 45:169–180PubMedCrossRefGoogle Scholar
  166. Xie W, Schultz MD, Lister R, Hou Z, Rajagopal N, Ray P, Whitaker JW, Tian S, Hawkins RD, Leung D et al (2013) Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 153:1134–1148PubMedPubMedCentralCrossRefGoogle Scholar
  167. Yaffe E, Farkash-Amar S, Polten A, Yakhini Z, Tanay A, Simon I (2010) Comparative analysis of DNA replication timing reveals conserved large-scale chromosomal architecture. PLoS Genet 6:e1001011PubMedPubMedCentralCrossRefGoogle Scholar
  168. Yamazaki S, Ishii A, Kanoh Y, Oda M, Nishito Y, Masai H (2012) Rif1 regulates the replication timing domains on the human genome. EMBO J 31:3667–3677PubMedPubMedCentralCrossRefGoogle Scholar
  169. Yang SC, Rhind N, Bechhoefer J (2010) Modeling genome-wide replication kinetics reveals a mechanism for regulation of replication timing. Mol Syst Biol 6:404PubMedPubMedCentralGoogle Scholar
  170. Yasuhara JC, DeCrease CH, Wakimoto BT (2005) Evolution of heterochromatic genes of Drosophila. Proc Natl Acad Sci U S A 102:10958–10963PubMedPubMedCentralCrossRefGoogle Scholar
  171. Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T, Sandstrom R, Ma Z, Davis C, Pope BD et al (2014) A comparative encyclopedia of DNA elements in the mouse genome. Nature 515:355–364PubMedPubMedCentralCrossRefGoogle Scholar
  172. Zhang J, Xu F, Hashimshony T, Keshet I, Cedar H (2002) Establishment of transcriptional competence in early and late S phase. Nature 420:198–202PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Peiyao A. Zhao
    • 1
  • Juan Carlos Rivera-Mulia
    • 1
  • David M. Gilbert
    • 1
    • 2
    Email author
  1. 1.Department of Biological ScienceFlorida State UniversityTallahasseeUSA
  2. 2.Center for Genomics and Personalized MedicineFlorida State UniversityTallahasseeUSA

Personalised recommendations