Review Article | Published:

A changing paradigm of transcriptional memory propagation through mitosis


The highly reproducible inheritance of chromosomes during mitosis in mammalian cells involves nuclear envelope breakdown, increased chromatin compaction, loss of long-range intrachromosomal interactions, loss of enhancer–promoter proximity, displacement of many transcription regulators from the chromatin and a marked decrease in RNA synthesis. Despite these dramatic changes in the mother cell, daughter cells are able to faithfully re-establish the parental chromatin and gene expression features characteristic of the cell type. Pioneering studies of mitotic chromatin signatures showed that despite global repression of transcription, the Hsp70 gene promoter retains an open chromatin conformation, which was proposed to allow the reactivation of the Hsp70 gene upon completion of mitosis — a phenomenon termed mitotic bookmarking. It was later shown that various cell-type-specific transcription factors, such as GATA-binding factor 1 (GATA1) in erythroblasts and forkhead box protein A1 (FOXA1) in hepatocytes, remain bound at a subset of their interphase binding sites in mitosis. Such bookmarking transcription factors remain on chromosomes in mitosis and have been shown to enable a subset of genes to be reactivated in a timely fashion upon mitotic exit. In addition, sensitive new methods to measure transcription revealed that mitotic cells retain residual transcription at a large number of genes. Furthermore, genes recover their interphase level of transcription in distinct waves. Thus, gene expression is precisely regulated as cells pass through mitosis to ensure faithful propagation of cell identity and function through cellular generations.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Naumova, N. et al. Organization of the mitotic chromosome. Science 342, 948–953 (2013).

  2. 2.

    Hsiung, C. C. et al. A hyperactive transcriptional state marks genome reactivation at the mitosis-G1 transition. Genes Dev. 30, 1423–1439 (2016). This study, using ChIP–seq and Capture-C in murine erythroblasts in mitosis and during mitotic exit, shows a large spike in Pol II binding and a re-formation of enhancer–promoter loops approximately 90 minutes into mitotic exit.

  3. 3.

    Martinez-Balbas, M. A., Dey, A., Rabindran, S. K., Ozato, K. & Wu, C. Displacement of sequence-specific transcription factors from mitotic chromatin. Cell 83, 29–38 (1995).

  4. 4.

    Guo, J., Turek, M. E. & Price, D. H. Regulation of RNA polymerase II termination by phosphorylation of Gdown1. J. Biol. Chem. 289, 12657–12665 (2014).

  5. 5.

    Dovat, S. et al. A common mechanism for mitotic inactivation of C2H2 zinc finger DNA-binding domains. Genes Dev. 16, 2985–2990 (2002).

  6. 6.

    Zaidi, S. K. et al. Mitotic bookmarking of genes: a novel dimension to epigenetic control. Nat. Rev. Genet. 11, 583–589 (2010).

  7. 7.

    Egli, D., Birkhoff, G. & Eggan, K. Mediators of reprogramming: transcription factors and transitions through mitosis. Nat. Rev. Mol. Cell Biol. 9, 505–516 (2008).

  8. 8.

    Kadauke, S. & Blobel, G. A. Mitotic bookmarking by transcription factors. Epigenet. Chromatin 6, 6 (2013).

  9. 9.

    Festuccia, N., Gonzalez, I., Owens, N. & Navarro, P. Mitotic bookmarking in development and stem cells. Development 144, 3633–3645 (2017).

  10. 10.

    Zaret, K. S. Genome reactivation after the silence in mitosis: recapitulating mechanisms of development? Dev. Cell 29, 132–134 (2014).

  11. 11.

    Michelotti, E. F., Sanford, S. & Levens, D. Marking of active genes on mitotic chromosomes. Nature 388, 895–899 (1997).

  12. 12.

    Xing, H. et al. Mechanism of hsp70i gene bookmarking. Science 307, 421–423 (2005).

  13. 13.

    Xing, H., Vanderford, N. L. & Sarge, K. D. The TBP-PP2A mitotic complex bookmarks genes by preventing condensin action. Nat. Cell Biol. 10, 1318–1323 (2008).

  14. 14.

    Segil, N., Guermah, M., Hoffmann, A., Roeder, R. G. & Heintz, N. Mitotic regulation of TFIID: inhibition of activator-dependent transcription and changes in subcellular localization. Genes Dev. 10, 2389–2400 (1996).

  15. 15.

    Chen, D., Hinkley, C. S., Henry, R. W. & Huang, S. TBP dynamics in living human cells: constitutive association of TBP with mitotic chromosomes. Mol. Biol. Cell 13, 276–284 (2002).

  16. 16.

    Christova, R. & Oelgeschlager, T. Association of human TFIID-promoter complexes with silenced mitotic chromatin in vivo. Nat. Cell Biol. 4, 79–82 (2002).

  17. 17.

    Young, D. W. et al. Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2. Nature 445, 442–446 (2007).

  18. 18.

    Kadauke, S. et al. Tissue-specific mitotic bookmarking by hematopoietic transcription factor GATA1. Cell 150, 725–737 (2012).

  19. 19.

    Caravaca, J. M. et al. Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. Genes Dev. 27, 251–260 (2013). This study shows that FOXA1 quantitatively remains on mitotic chromosomes via primarily nonspecific DNA and nucleosomal interactions while also retaining specific binding at a subset of sites.

  20. 20.

    Verdeguer, F. et al. A mitotic transcriptional switch in polycystic kidney disease. Nat. Med. 16, 106–110 (2010).

  21. 21.

    Lerner, J. et al. Human mutations affect the epigenetic/bookmarking function of HNF1B. Nucleic Acids Res. 44, 8097–8111 (2016). This study shows that formaldehyde causes artefactual cytoplasmic localization of the bookmarking factor HNF1β and that inhibition of importin delays the mitotic relocalization of a temperature-sensitive HNF1β mutant to chromatin.

  22. 22.

    Festuccia, N. et al. Mitotic binding of Esrrb marks key regulatory regions of the pluripotency network. Nat. Cell Biol. 18, 1139–1148 (2016). In this study, an ESRRβ–GFP fusion is stably integrated into embryonic stem cells and live imaging showed that it is highly dynamic in mitosis and associates with both specific and nonspecific binding sites.

  23. 23.

    Teves, S. S. et al. A dynamic mode of mitotic bookmarking by transcription factors. eLife 5, e22280 (2016).

  24. 24.

    Blobel, G. A. et al. A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit. Mol. Cell 36, 970–983 (2009).

  25. 25.

    Yang, J., Sung, E., Donlin-Asp, P. G. & Corces, V. G. A subset of Drosophila Myc sites remain associated with mitotic chromosomes colocalized with insulator proteins. Nat. Commun. 4, 1464 (2013).

  26. 26.

    Dey, A., Nishiyama, A., Karpova, T., McNally, J. & Ozato, K. Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription. Mol. Biol. Cell 20, 4899–4909 (2009).

  27. 27.

    Deluz, C. et al. A role for mitotic bookmarking of SOX2 in pluripotency and differentiation. Genes Dev. 30, 2538–2550 (2016). This study performs mitosis-specific knockdown of SOX2, showing that mitotic bookmarking by SOX2 contributes to pluripotency maintenance and is necessary for neuroectodermal differentiation but is dispensable for reprogramming towards induced pluripotency.

  28. 28.

    Burke, L. J. et al. CTCF binding and higher order chromatin structure of the H19 locus are maintained in mitotic chromatin. EMBO J. 24, 3291–3300 (2005).

  29. 29.

    Wong, M. M. et al. Promoter-bound p300 complexes facilitate post-mitotic transmission of transcriptional memory. PLOS ONE 9, e99989 (2014).

  30. 30.

    Zhao, R., Nakamura, T., Fu, Y., Lazar, Z. & Spector, D. L. Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activation. Nat. Cell Biol. 13, 1295–1304 (2011).

  31. 31.

    Pallier, C. et al. Association of chromatin proteins high mobility group box (HMGB) 1 and HMGB2 with mitotic chromosomes. Mol. Biol. Cell 14, 3414–3426 (2003).

  32. 32.

    Teves, S. S. et al. A stable mode of bookmarking by TBP recruits RNA polymerase II to mitotic chromosomes. eLife 7, e35621 (2018). This study focuses on the promoter binding factor TBP in mitotic bookmarking, emphasizing the role of the promoter region in mitotic memory.

  33. 33.

    Hsiung, C. C. et al. Genome accessibility is widely preserved and locally modulated during mitosis. Genome Res. 25, 213–225 (2015).

  34. 34.

    Chen, D. et al. Condensed mitotic chromatin is accessible to transcription factors and chromatin structural proteins. J. Cell Biol. 168, 41–54 (2005).

  35. 35.

    Ou, H. D. et al. ChromEMT: visualizing 3D chromatin structure and compaction in interphase and mitotic cells. Science 357, eaag0025 (2017). This study establishes an electron microscopy tomography of chromatin (ChromEMT) to show that overall, the structure of chromosome fibres is unaltered in mitotic chromosomes and that chromatin chains bend at various lengths to perform the high level of compaction reached in mitotic chromosomes.

  36. 36.

    Valls, E., Sanchez-Molina, S. & Martinez-Balbas, M. A. Role of histone modifications in marking and activating genes through mitosis. J. Biol. Chem. 280, 42592–42600 (2005).

  37. 37.

    Liu, Y. et al. Widespread mitotic bookmarking by histone marks and transcription factors in pluripotent stem cells. Cell Rep. 19, 1283–1293 (2017). This study shows that mitotic-specific knockdown of OCT4 impairs pluripotency maintenance and reveals that H3K27ac in mitosis marks promoters of housekeeping genes and enhancers of pluripotency genes.

  38. 38.

    Wilkins, B. J. et al. A cascade of histone modifications induces chromatin condensation in mitosis. Science 343, 77–80 (2014).

  39. 39.

    Javasky, E. et al. Study of the mitotic chromatin shows involvement of histone modifications in bookmarking and reveals nucleosome deposition patterns. Preprint at (2017).

  40. 40.

    Wang, F. & Higgins, J. M. Histone modifications and mitosis: countermarks, landmarks, and bookmarks. Trends Cell Biol. 23, 175–184 (2013).

  41. 41.

    Kouskouti, A. & Talianidis, I. Histone modifications defining active genes persist after transcriptional and mitotic inactivation. EMBO J. 24, 347–357 (2005).

  42. 42.

    Liu, Y. et al. Transcriptional landscape of the human cell cycle. Proc. Natl Acad. Sci. USA 114, 3473–3478 (2017).

  43. 43.

    Reinberg, D. & Vales, L. D. Chromatin domains rich in inheritance. Science 361, 33–34 (2018).

  44. 44.

    Prescott, D. M. & Bender, M. A. Synthesis of RNA and protein during mitosis in mammalian tissue culture cells. Exp. Cell Res. 26, 260–268 (1962).

  45. 45.

    Parsons, G. G. & Spencer, C. A. Mitotic repression of RNA polymerase II transcription is accompanied by release of transcription elongation complexes. Mol. Cell. Biol. 17, 5791–5802 (1997).

  46. 46.

    Matsui, S. I., Weinfeld, H. & Sandberg, A. A. Quantitative conservation of chromatin-bound RNA polymerases I and II in mitosis. Implications for chromosome structure. J. Cell Biol. 80, 451–464 (1979).

  47. 47.

    Liang, K. et al. Mitotic transcriptional activation: clearance of actively engaged Pol II via transcriptional elongation control in mitosis. Mol. Cell 60, 435–445 (2015).

  48. 48.

    Liu, H. et al. Mitotic transcription installs Sgo1 at centromeres to coordinate chromosome segregation. Mol. Cell 59, 426–436 (2015).

  49. 49.

    Chen, C. C. et al. Establishment of centromeric chromatin by the CENP-A assembly factor CAL1 requires FACT-mediated transcription. Dev. Cell 34, 73–84 (2015).

  50. 50.

    Gariglio, P., Buss, J. & Green, M. H. Sarkosyl activation of RNA polymerase activity in mitotic mouse cells. FEBS Lett. 44, 330–333 (1974).

  51. 51.

    Johnson, T. C. & Holland, J. J. Ribonucleic acid and protein synthesis in mitotic HeLa cells. J. Cell Biol. 27, 565–574 (1965).

  52. 52.

    Konrad, C. G. Protein synthesis and rna synthesis during mitosis in animal cells. J. Cell Biol. 19, 267–277 (1963).

  53. 53.

    Palozola, K. C. et al. Mitotic transcription and waves of gene reactivation during mitotic exit. Science 358, 119–122 (2017). This study uses a new method to detect low-level transcription occurring globally during mitosis and reveals that enhancer usage correlates with dynamic gene reactivation during mitotic exit.

  54. 54.

    Booth, D. G. et al. 3D-CLEM reveals that a major portion of mitotic chromosomes is not chromatin. Mol. Cell 64, 790–802 (2016).

  55. 55.

    Ohta, S. et al. The protein composition of mitotic chromosomes determined using multiclassifier combinatorial proteomics. Cell 142, 810–821 (2010).

  56. 56.

    Cuylen, S. et al. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature 535, 308–312 (2016).

  57. 57.

    Gautier, T., Robert-Nicoud, M., Guilly, M. N. & Hernandez-Verdun, D. Relocation of nucleolar proteins around chromosomes at mitosis. A study by confocal laser scanning microscopy. J. Cell Sci. 102, 729–737 (1992).

  58. 58.

    Xiao, H. et al. Molecular basis of CENP-C association with the CENP-A nucleosome at yeast centromeres. Genes Dev. 31, 1958–1972 (2017).

  59. 59.

    Soderholm, J. F. et al. Importazole, a small molecule inhibitor of the transport receptor importin-β. ACS Chem. Biol. 6, 700–708 (2011).

  60. 60.

    Clarke, P. R. & Zhang, C. Spatial and temporal coordination of mitosis by Ran GTPase. Nat. Rev. Mol. Cell Biol. 9, 464–477 (2008).

  61. 61.

    Vankova Hausnerova, V. & Lanctot, C. Transcriptional output transiently spikes upon mitotic exit. Sci. Rep. 7, 12607 (2017).

  62. 62.

    Iwasaki, H. et al. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev. 20, 3010–3021 (2006).

  63. 63.

    Deluz, C., Strebinger, D., Friman, E. T. & Suter, D. M. The elusive role of mitotic bookmarking in transcriptional regulation: insights from Sox2. Cell Cycle 16, 601–606 (2017).

  64. 64.

    Osterwalder, M. et al. Enhancer redundancy provides phenotypic robustness in mammalian development. Nature 554, 239–243 (2018).

  65. 65.

    Arnold, P. L. A reducing role for boron. Nature 502, 458 (2013).

  66. 66.

    Dileep, V. et al. 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, 1104–1113 (2015).

  67. 67.

    Pope, B. D. et al. Topologically associating domains are stable units of replication-timing regulation. Nature 515, 402–405 (2014).

  68. 68.

    Hansen, R. S. et al. Sequencing newly replicated DNA reveals widespread plasticity in human replication timing. Proc. Natl Acad. Sci. USA 107, 139–144 (2010).

  69. 69.

    Hiratani, I. et al. Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis. Genome Res. 20, 155–169 (2010).

  70. 70.

    Pope, B. D. et al. Replication-timing boundaries facilitate cell-type and species-specific regulation of a rearranged human chromosome in mouse. Hum. Mol. Genet. 21, 4162–4170 (2012).

  71. 71.

    Rivera-Mulia, J. C. et al. Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells. Genome Res. 25, 1091–1103 (2015).

  72. 72.

    Ryba, T. et al. Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res. 20, 761–770 (2010).

  73. 73.

    Jacinto, F. V., Benner, C. & Hetzer, M. W. The nucleoporin Nup153 regulates embryonic stem cell pluripotency through gene silencing. Genes Dev. 29, 1224–1238 (2015).

  74. 74.

    Ibarra, A., Benner, C., Tyagi, S., Cool, J. & Hetzer, M. W. Nucleoporin-mediated regulation of cell identity genes. Genes Dev. 30, 2253–2258 (2016).

  75. 75.

    Toda, T. et al. Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells. Cell Stem Cell 21, 618–634.e7 (2017).

  76. 76.

    Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008).

  77. 77.

    Prasanth, K. V., Sacco-Bubulya, P. A., Prasanth, S. G. & Spector, D. L. Sequential entry of components of the gene expression machinery into daughter nuclei. Mol. Biol. Cell 14, 1043–1057 (2003).

  78. 78.

    Jao, C. Y. & Salic, A. Exploring RNA transcription and turnover in vivo by using click chemistry. Proc. Natl Acad. Sci. USA 105, 15779–15784 (2008).

  79. 79.

    Yan, J., Xu, L., Crawford, G., Wang, Z. & Burgess, S. M. The forkhead transcription factor FoxI1 remains bound to condensed mitotic chromosomes and stably remodels chromatin structure. Mol. Cell. Biol. 26, 155–168 (2006).

  80. 80.

    Young, D. W. et al. Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2. Proc. Natl Acad. Sci. USA 104, 3189–3194 (2007).

  81. 81.

    Lake, R. L., Tsai, R. F., Choi, I., Won, K. J. & Fan, H. Y. Specific mitotic chromatin association of the major notch effector RBPJ and its implication for transcriptional memory. NCBI (2013).

  82. 82.

    Lodhi, N., Ji, Y. & Tulin, A. Mitotic bookmarking: maintaining post-mitotic reprogramming of transcription reactivation. Curr. Mol. Biol. Rep. 2, 10–16 (2016).

  83. 83.

    Calderon, M. R. et al. Ligand-dependent corepressor contributes to transcriptional repression by C2H2 zinc-finger transcription factor ZBRK1 through association with KRAB-associated protein-1. Nucleic Acids Res. 42, 7012–7027 (2014).

  84. 84.

    Lodhi, N., Kossenkov, A. V. & Tulin, A. V. Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark. Nucleic Acids Res. 42, 7028–7038 (2014).

  85. 85.

    Kara, N., Hossain, M., Prasanth, S. G. & Stillman, B. Orc1 binding to mitotic chromosomes precedes spatial patterning during G1 phase and assembly of the origin recognition complex in human cells. J. Biol. Chem. 290, 12355–12369 (2015).

  86. 86.

    Arora, M., Packard, C. Z., Banerjee, T. & Parvin, J. D. RING1A and BMI1 bookmark active genes via ubiquitination of chromatin-associated proteins. Nucleic Acids Res. 44, 2136–2144 (2016).

Download references


The authors thank P. Navarro (Institut Pasteur) for comments on the manuscript and M. Song for help in its preparation. Research on mitotic transcription has been supported by US National Institutes of Health (NIH) grant T32GM00812 to K.C.P., by Fondation pour la Recherche Médicale grant 40334 to J.L. and by NIH grant GM36477 to K.S.Z.

Reviewer information

Nature Reviews Molecular Cell Biology thanks D. Suter, P. Navarro and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

The authors contributed equally to all aspects of the article.

Competing interests

The authors declare no competing interests.

Correspondence to Kenneth S. Zaret.


Epigenetic control of gene expression

Mechanisms independent of DNA alterations through which the gene expression programme particular to a cell type is recapitulated in daughter cells after cell division.


A method of detecting where proteins are bound to DNA on the basis of their accessibility to enzymes such as DNase I or chemicals such as DMS or potassium permanganate.

General transcription factors

Proteins that act at promoters to enable transcription of many classes of genes.

Promoter transcription factors

General transcription factors that localize to promoters.

Architectural transcription factors

Transcription factors, such as CTCF (CCCTC-binding factor), that bring regions of the genome together to form higher-order chromatin structures, which have important roles in gene expression regulation.


A modified enzyme that binds to a synthetic ligand target and can be fused to a protein of interest for visualization.

Pioneer factor

Transcription factor that can directly bind nucleosomal DNA in chromatin.

Topologically associated domains

(TADs). Boundary-insulated chromosomal segments within which sequences preferentially contact each other.

Housekeeping genes

Genes that are responsible for the general functions of a cell, such as growth and metabolism, independent of the cell’s specialized function.

Click reaction

The copper-catalysed conjugation of an azide with an alkyne to yield a five-part heteroatom ring.

Interphase contamination

Transcriptional signal in a population of mitotic cells that results from contaminating interphase cells in that population. Importantly, for studies of mitotic transcription, the high transcriptional activity of the contaminating interphase cells, relative to the low level that occurs in mitotic cells, can lead to overestimation of transcription during mitosis.

Spike-in controls

Short, known sequences of DNA or RNA that are added to a sample at a known quantity at the beginning of a high-throughput sequencing assay to help normalize for synthesis and recovery when comparing different samples.

DNase I hypersensitivity

The ability of a segment of DNA in chromatin to be digested by DNase I owing to the accessibility of this segment (lack of local compaction).

Assay for transposase-accessible chromatin with sequencing

(ATAC–seq). A method that uses the Tn5 transposase to probe the genome for accessibility.

Amphiphilic protein

A protein that is hydrophobic on one end and hydrophilic on the other end.

Histone variant

A substitute for one of the canonical histones in a nucleosome.


A compound that prevents microtubule polymerization, thereby blocking the formation of the metaphase plate.

Enhancer RNAs

(eRNAs). RNAs that are generated from the site of enhancer sequences, presumably as a by-product of Pol II activity.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading

Fig. 1: Mitotic bookmarking by transcription factors.
Fig. 2: Histone modifications in mitosis.
Fig. 3: Mitotic cells maintain low levels of transcription.
Fig. 4: Transcription reactivation during mitotic exit.