Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

See all formats and pricing
More options …
Ahead of print


Ageing and sources of transcriptional heterogeneity

Chrysa Nikopoulou
  • Max Planck Research Group ‘Chromatin and Ageing’, Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Swati Parekh
  • Max Planck Research Group ‘Chromatin and Ageing’, Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Peter TessarzORCID iD: https://orcid.org/0000-0002-6953-9835
  • Corresponding author
  • Max Planck Research Group ‘Chromatin and Ageing’, Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
  • Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
  • orcid.org/0000-0002-6953-9835
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2019-04-22 | DOI: https://doi.org/10.1515/hsz-2018-0449


Cellular heterogeneity is an important contributor to biological function and is employed by cells, tissues and organisms to adapt, compensate, respond, defend and/or regulate specific processes. Research over the last decades has revealed that transcriptional noise is a major driver for cell-to-cell variability. In this review we will discuss sources of transcriptional variability, in particular bursting of gene expression and how it could contribute to cellular states and fate decisions. We will highlight recent developments in single cell sequencing technologies that make it possible to address cellular heterogeneity in unprecedented detail. Finally, we will review recent literature, in which these new technologies are harnessed to address pressing questions in the field of ageing research, such as transcriptional noise and cellular heterogeneity in the course of ageing.

Keywords: cellular heterogeneity; chromatin dynamics; epigenetics; single-cell biology; stochastic gene expression; transcriptional noise


  • Adelman, K. and Lis, J.T. (2012). Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat. Rev. Genet. 13, 720–731.CrossrefPubMedGoogle Scholar

  • Aguayo-Mazzucato, C., van Haaren, M., Mruk, M., Lee Jr., T.B., Crawford, C., Hollister-Lock, J., Sullivan, B.A., Johnson, J.W., Ebrahimi, A., Dreyfuss, J.M., et al. (2017). β Cell aging markers have heterogeneous distribution and are induced by insulin resistance. Cell Metab. 25, 898–910.PubMedCrossrefGoogle Scholar

  • Anderson, L.M. and Yang, H. (2008). DNA looping can enhance lysogenic CI transcription in phage lambda. Proc. Natl. Acad. Sci. USA 105, 5827–5832.CrossrefGoogle Scholar

  • Angelidis, I., Simon, L.M., Fernandez, I.E., Strunz, M., Mayr, CH., Greiffo, F.R., Tsitsiridis, G., Graf, E., Strom, T.M., Nagendran, M., et al. (2019). An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. Nat. Commun. 10, 963.PubMedCrossrefGoogle Scholar

  • Angermueller, C., Clark, S.J., Lee, H.J., Macaulay, I.C., Teng, M.J., Hu, T.X., Krueger, F., Smallwood, S., Ponting, C.P., Voet, T., et al. (2016). Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity. Nat. Methods 13, 229–232.CrossrefPubMedGoogle Scholar

  • Apostolou, E. and Thanos, D. (2008). Virus Infection Induces NF-kB-dependent interchromosomal associations mediating monoallelic IFN-b gene expression. Cell 134, 85–96.CrossrefGoogle Scholar

  • Avery, O.T., Macleod, C.M., and McCarty, M. (1944). Studies on the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from Pneumococcus type III. J. Exp. Med. 79, 137–158.PubMedCrossrefGoogle Scholar

  • Bahar, R., Halpern, K., and Itzkovitz, S. (2006). Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441, 1011–1014.PubMedCrossrefGoogle Scholar

  • Balaeff, A., Mahadevan, L., and Schulten, K. (2004). Structural basis for cooperative DNA binding by CAP and lac repressor. Structure 12, 123–132.PubMedCrossrefGoogle Scholar

  • Bartman, C.R., Hsu, S.C., Hsiung, C.C.-S., Raj, A., and Blobel, G.A. (2016). Enhancer regulation of transcriptional bursting parameters revealed by forced chromatin looping. Mol. Cell 62, 237–247.CrossrefPubMedGoogle Scholar

  • Benninger, R.K.P., Dorrell, C., Hodson, D.J., and Rutter, G.A. (2018). The impact of pancreatic b cell heterogeneity on type 1 diabetes pathogenesis. Curr. Diab. Rep. 18, 112.CrossrefGoogle Scholar

  • Bochkis, I.M., Przybylski, D., Chen, J., and Regev, A. (2014). Changes in nucleosome occupancy associated with metabolic alterations in aged mammalian liver. Cell Rep. 9, 996–1006.PubMedCrossrefGoogle Scholar

  • Booth, L.N. and Brunet, A. (2016). The aging epigenome. Mol. Cell 62, 728–744.CrossrefPubMedGoogle Scholar

  • Bothma, J.P., Garcia, H.G., Esposito, E., Schlissel, G., Gregor, T., and Levine, M. (2014). Dynamic regulation of eve stripe 2 expression reveals transcriptional bursts in living Drosophila embryos. Proc. Natl. Acad. Sci. USA 111, 10598–10603.CrossrefGoogle Scholar

  • Brown, C.R., Mao, C., Falkovskaia, E., Jurica, M.S., and Boeger, H. (2013). Linking stochastic fluctuations in chromatin structure and gene expression. PLoS Biol. 11, e1001621.PubMedCrossrefGoogle Scholar

  • Buenrostro, J.D., Wu, B., Litzenburger, U.M., Ruff, D., Gonzales, M.L., Snyder, M.P., Chang, H.Y., and Greenleaf, W.J. (2015). Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523, 486–490.PubMedCrossrefGoogle Scholar

  • Buettner, F., Natarajan, K.N., Casale, F.P., Proserpio, V., Scialdone, A., Theis, F.J., Teichmann, S.A., Marioni, J.C., and Stegle, O. (2015). Computational analysis of cell-to-cell heterogeneity in single-cell RNA-sequencing data reveals hidden subpopulations of cells. Nat. Biotechnol. 33, 155.CrossrefPubMedGoogle Scholar

  • Carter, D., Chakalova, L., Osborne, C.S., Dai, Y.-F., and Fraser, P. (2002). Long-range chromatin regulatory interactions in vivo. Nat. Genet. 32, 623–626.CrossrefPubMedGoogle Scholar

  • Chambers, I., Silva, J., Colby, D., Nichols, J., Nijmeijer, B., Robertson, M., Vrana, J., Jones, K., Grotewold, L., and Smith, A. (2007). Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234.CrossrefPubMedGoogle Scholar

  • Chang, H.H., Hemberg, M., Barahona, M., Ingber, D.E., and Huang, S. (2008). Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453, 544–547.CrossrefPubMedGoogle Scholar

  • Chess, A., Simon, I., Cedar, H., and Axel, R. (1994). Allelic inactivation regulates olfactory receptor gene expression. Cell 78, 823–834.PubMedCrossrefGoogle Scholar

  • Cheung, P., Vallania, F., Warsinske, H.C., Donato, M., Schaffert, S., Chang, S.E., Dvorak, M., Dekker, C.L., Davis, M.M., Utz, P.J., et al. (2018). Single-cell chromatin modification profiling reveals increased epigenetic variations with aging. Cell 173, 1385–1397.CrossrefPubMedGoogle Scholar

  • Choi, J., Huebner, A.J., Clement, K., Walsh, R.M., Savol, A., Lin, K., Gu, H., Di Stefano, B., Brumbaugh, J., Kim, S.Y., et al. (2017). Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells. Nature 548, 219–223.PubMedCrossrefGoogle Scholar

  • Clark, S.J., Argelaguet, R., Kapourani, C.A., Stubbs, T.M., Lee, H.J., Alda-Catalinas, C., Krueger, F., Sanguinetti, G., Kelsey, G., Marioni, J.C., et al. (2018). scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat. Commun. 9, 781.PubMedCrossrefGoogle Scholar

  • Corrigan, A.M., Tunnacliffe, E., Cannon, D., and Chubb, J.R. (2016). A continuum model of transcriptional bursting. eLife 5, e13051.CrossrefPubMedGoogle Scholar

  • Crick, F. (1970). Central dogma of molecular biology. Nature 227, 561–563.CrossrefPubMedGoogle Scholar

  • Cusanovich, D.A., Daza, R., Adey, A., Pliner, H.A., Christiansen, L., Gunderson, K.L., Steemers, F.J., Trapnell, C., and Shendure, J. (2015). Multiplex single cell profiling of chromatin accessibility by combinatorial cellular indexing. Science 348, 910–914.PubMedCrossrefGoogle Scholar

  • Dar, R.D., Razooky, B.S., Singh, A., Trimeloni, T.V., McCollum, J.M., Cox, C.D., Simpson, M.L., and Weinberger, L.S. (2012). Transcriptional burst frequency and burst size are equally modulated across the human genome. Proc. Natl. Acad. Sci. USA 109, 17454–17459.CrossrefGoogle Scholar

  • Darzacq, X., Shav-Tal, Y., de Turris, V., Brody, Y., Shenoy, S.M., Phair, R.D., and Singer, R.H. (2007). In vivo dynamics of RNA polymerase II transcription. Nat. Struct. Mol. Biol. 14, 796–806.PubMedCrossrefGoogle Scholar

  • Das, D., Dey, S., Brewster, R.C., and Choubey, S. (2017). Effect of transcription factor resource sharing on gene expression noise. PLoS Comput. Biol. 13, e1005491.PubMedCrossrefGoogle Scholar

  • Davie, K., Janssens, J., Koldere, D., De Waegeneer, M., Pech, U., Kreft, K., Albar, S., Makhzami, S., Christiaens, V., Bravo González-Blas, C., et al. (2018). A single-cell transcriptome atlas of the aging Drosophila brain. Cell 174, 982–998.CrossrefPubMedGoogle Scholar

  • de Krom, M., van de Corput, M., von Lindern, M., Grosveld, F., and Strouboulis, J. (2002). Stochastic patterns in globin gene expression are established prior to transcriptional activation and are clonally inherited. Mol. Cell 9, 1319–1326.PubMedCrossrefGoogle Scholar

  • Deng, Q., Ramsköld, D., Reinius, B., and Sandberg, R. (2014). Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells. Science 343, 193–196.PubMedCrossrefGoogle Scholar

  • Dodd, I.B., Shearwin, K.E., Perkins, A.J., Burr, T., Hochschild, A., and Egan, J.B. (2004). Cooperativity in long-range gene regulation by the lambda CI repressor. Genes Dev. 18, 344–354.CrossrefPubMedGoogle Scholar

  • Elowitz, M.B., Levine, A.J., Siggia, E.D., and Swain, P.S. (2002). Stochastic gene expression in a single cell. Science 297, 1183–1186.CrossrefGoogle Scholar

  • Enge, M., Arda, H.E., Mignardi, M., Beausang, J., Bottino, R., Kim, S.K., and Quake, S.R. (2017). Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell 171, 321–330.e14.Google Scholar

  • Femino, A.M., Fay, F.S., Fogarty, K., and Singer, R.H. (1998). Visualization of single RNA transcripts in situ. Science 280, 585–590.CrossrefPubMedGoogle Scholar

  • Feser, J. and Tyler, J. (2011). Chromatin structure as a mediator of aging. FEBS Lett. 585, 2041–2048.CrossrefPubMedGoogle Scholar

  • Feser, J., Truong, D., Das, C., Carson, J.J., Kieft, J., Harkness, T., and Tyler, J.K. (2010). Elevated histone expression promotes life span extension. Mol. Cell 39, 724–735.PubMedCrossrefGoogle Scholar

  • Florian, M.C., Dörr, K., Niebel, A., Daria, D., Schrezenmeier, H., Rojewski, M., Filippi, M.D., Hasenberg, A., Gunzer, M, Scharffetter-Kochanek, K., et al. (2012). Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530.CrossrefPubMedGoogle Scholar

  • Fritzsch, C., Baumgärtner, S., Kuban, M., Steinshorn, D., Reid, G., and Legewie, S. (2018). Estrogen-dependent control and cell-to-cell variability of transcriptional bursting. Mol. Syst. Biol. 14, e7678.PubMedCrossrefGoogle Scholar

  • Fukaya, T., Lim, B., and Levine, M. (2016). Enhancer control of transcriptional bursting. Cell 166, 358–368.CrossrefPubMedGoogle Scholar

  • Gehring, N.H., Wahle, E., and Fischer, U. (2017). Deciphering the mRNP code: RNA-bound determinants of post-transcriptional gene regulation. Trends Biochem. Sci. 42, 369–382.PubMedCrossrefGoogle Scholar

  • Golding, I., Paulsson, J., Zawilski, S.M., and Cox, E.C. (2005). Real-time kinetics of gene activity in individual bacteria. Cell 123, 1025–1036.PubMedCrossrefGoogle Scholar

  • Guo, R., Ye, X., Yang, J., Zhou, Z., Tian, C., Wang, H., Wang, H., Fu, H., Liu, C., Zeng, M., et al. (2018). Feeders facilitate telomere maintenance and chromosomal stability of embryonic stem cells. Nat. Commun. 9, 2620.CrossrefPubMedGoogle Scholar

  • Hainer, S.J., Boskovic, A., Rando, O.J., and Fazzio, T.G. (2018). Profiling of pluripotency factors in individual stem cells and early embryos. bioRxiv, 286351.Google Scholar

  • Hatano, S.-Y., Tada, M., Kimura, H., Yamaguchi, S., Kono, T., Nakano, T., Suemori, H., Nakatsuji, N., and Tada, T. (2005). Pluripotential competence of cells associated with Nanog activity. Mech. Dev. 122, 67–79.PubMedCrossrefGoogle Scholar

  • Holländer, G.A., Zuklys, S., Morel, C., Mizoguchi, E., Mobisson, K., Simpson, S., Terhorst, C., Wishart, W., Golan, D.E., Bhan, A.K., et al. (1998). Monoallelic expression of the interleukin-2 locus. Science 279, 2118–2121.PubMedCrossrefGoogle Scholar

  • Hou, Y., Guo, H., Cao, C., Li, X., Hu, B., Zhu, P., Wu, X., Wen, L., Tang, F., Huang, Y., et al. (2016). Single-cell triple omics sequencing reveals genetic, epigenetic, and transcriptomic heterogeneity in hepatocellular carcinomas. Cell Res. 26, 304–319.CrossrefPubMedGoogle Scholar

  • Hu, Z., Chen, K., Xia, Z., Chavez, M., Pal, S., Seol, J.-H., Chen, C.-C., Li, W., and Tyler, J.K. (2014). Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging. Genes Dev. 28, 396–408.PubMedCrossrefGoogle Scholar

  • Hu, Y., Huang, K., An, Q., Du, G., Hu, G., Xue, J., Zhu, X., Wang, C.Y., Xue, Z., Fan, G. (2016). Simultaneous profiling of transcriptome and DNA methylome from a single cell. Genome Biol. 17, 88.CrossrefPubMedGoogle Scholar

  • Jones, P.A. (2012). Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492.CrossrefPubMedGoogle Scholar

  • Kaern, M., Elston, T.C., Blake, W.J., and Collins, J.J. (2005). Stochasticity in gene expression: from theories to phenotypes. Nat. Rev. Genet. 6, 451–464.CrossrefPubMedGoogle Scholar

  • Katsuta, H., Aguayo-Mazzucato, C., Katsuta, R., Akashi, T., Hollister-Lock, J., Sharma, A.J., Bonner-Weir, S., and Weir, G.C. (2012). Subpopulations of GFP-marked mouse pancreatic β-cells differ in size, granularity, and insulin secretion. Endocrinology 153, 5180–5187.CrossrefPubMedGoogle Scholar

  • Kellogg, R.A. and Tay, S. (2015). Noise facilitates transcriptional control under dynamic inputs. Cell 160, 381–392.CrossrefPubMedGoogle Scholar

  • Kelsey, G., Stegle, O., and Reik, W. (2017). Single-cell epigenomics: recording the past and predicting the future. Science 358, 69–75.CrossrefPubMedGoogle Scholar

  • Kim, J.K. and Marioni, J.C. (2013). Inferring the kinetics of stochastic gene expression from single-cell RNA-sequencing data. Genome Biol. 14, R7.PubMedCrossrefGoogle Scholar

  • Kolodziejczyk, A.A., Kim, J.K., Svensson, V., Marioni, J.C., and Teichmann, S.A. (2015). The technology and biology of single-cell RNA sequencing. Mol. Cell 58, 610–620.CrossrefPubMedGoogle Scholar

  • Koohy, H., Bolland, D.J., Matheson, L.S., Schoenfelder, S., Stellat, C., Dimond, A., Varnai, C., Chovanec, P., Chessa, T., Denizot, J., et al. (2018). Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signalling as a hallmark of aging in developing B cells. Genome Biol. 19, 126.PubMedCrossrefGoogle Scholar

  • Kumar, R.M., Cahan, P., Shalek, A.K., Satija, R., DaleyKeyser, A., Li, H., Zhang, J., Pardee, K., Gennert, D., Trombetta, J.J., et al. (2014). Deconstructing transcriptional heterogeneity in pluripotent stem cells. Nature 516, 56–61.CrossrefPubMedGoogle Scholar

  • Lagha, M., Bothma, J.P., Esposito, E., Ng, S., Stefanik, L., Tsui, C., Johnston, J., Chen, K., Gilmour, D.S., Zeitlinger, J., et al. (2013). Paused Pol II coordinates tissue morphogenesis in the Drosophila embryo. Cell 153, 976–987.PubMedCrossrefGoogle Scholar

  • La Manno, G., Soldatov, R., Zeisel, A., Braun, E., Hochgerner, H., Petukhov, V., Lidschreiber, K., Kastriti, M.E., Lönnerberg, P., Furlan, A., et al. (2018). RNA velocity of single cells. Nature 560, 494–498.CrossrefPubMedGoogle Scholar

  • Larson, D.R., Zenklusen, D., Wu, B., Chao, J.A., and Singer, R.H. (2011). Real-time observation of transcription initiation and elongation on an endogenous yeast gene. Science 332, 475–478.PubMedCrossrefGoogle Scholar

  • Larsson, A.J.M., Johnsson, P., Hagemann-Jensen, M., Hartmanis, L., Faridani, O.R., Reinius, B., Segerstolpe, A., Rivera, C.M., Ren, B., Sandberg, R., et al. (2019). Genomic encoding of transcriptional burst kinetics. Nature 565, 251–254.PubMedCrossrefGoogle Scholar

  • Liu, P., Song, R., Elison, G.L., Peng, W., and Acar, M. (2017). Noise reduction as an emergent property of single-cell aging. Nat. Commun. 8, 680.CrossrefPubMedGoogle Scholar

  • Lomvardas, S., Barnea, G., Pisapia, D.J., Mendelsohn, M., Kirkland, J., and Axel, R. (2006). Interchromosomal interactions and olfactory receptor choice. Cell 126, 403–413.CrossrefPubMedGoogle Scholar

  • Longo, V.D., Shadel, G.S., Kaeberlein, M., and Kennedy, B. (2012). Replicative and chronological aging in Saccharomyces cerevisiae. Cell Metab. 16, 18–31.CrossrefPubMedGoogle Scholar

  • Lyon, M.F. (1961). Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373.CrossrefPubMedGoogle Scholar

  • Martinez-Jimenez, C.P., Eling, N., Chen, H.C., Vallejos, C.A., Kolodziejczyk, A.A., Connor, F., Stojic, L., Rayner, T.F., Stubbington, M.J.T., Teichmann, S.A., et al. (2017). Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 355, 1433–1436.CrossrefPubMedGoogle Scholar

  • McKnight, S.L. and Miller Jr, O.L. (1979). Post-replicative nonribosomal transcription units in D. melanogaster embryos. Cell 17, 551–563.Google Scholar

  • Morelli, M.J., Ten Wolde, P.R., and Allen, R.J. (2009). DNA looping provides stability and robustness to the bacteriophage lambda switch. Proc. Natl. Acad. Sci. USA 106, 8101–8106.CrossrefGoogle Scholar

  • Moskowitz, D.M., Zhang, D.W., Hu, B., Le Saux, S., Yanes, R.E., Ye,Z., Buenrostro, J.D., Weyand, C.M., Greenleaf, W.J., and Goronzy, J.J. (2017). Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol. 2. doi: 10.1126/sciimmunol.aag0192.PubMedGoogle Scholar

  • Natoli, G., Saccani, S., Bosisio, D., and Marazzi, I. (2005). Interactions of NF-kB with chromatin: the art of being at the right place at the right time. Nat. Immunol. 6, 439–445.CrossrefGoogle Scholar

  • Newlands, S., Levitt, L.K., Robinson, C.S., Karpf, A.B., Hodgson, V.R., Wade, R.P., and Hardeman, E.C. (1998). Transcription occurs in pulses in muscle fibers. Genes Dev. 12, 2748–2758.CrossrefPubMedGoogle Scholar

  • Newman, J.R.S., Ghaemmaghami, S., Ihmels, J., Breslow, D.K., Noble, M., DeRisi, J.L., and Weissman, J.S. (2006). Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441, 840–846.CrossrefPubMedGoogle Scholar

  • Nicolas, D., Zoller, B., Suter, D.M., and Naef, F. (2018). Modulation of transcriptional burst frequency by histone acetylation. Proc. Natl. Acad. Sci. USA 115, 7153–7158.CrossrefGoogle Scholar

  • Nikopoulou, C., Panagopoulos, G., Sianidis, G., Psarra, E., Ford, E., and Thanos, D. (2018). The transcription factor ThPOK orchestrates stochastic interchromosomal interactions required for IFNB1 virus-inducible gene expression. Mol. Cell 71, 352–361.e5.PubMedCrossrefGoogle Scholar

  • Paulsson, J. (2005). Models of stochastic gene expression. Phys. Life Rev. 2, 157–175.CrossrefGoogle Scholar

  • Phillip, J.M., Wu, P.H., Gilkes, D.M., Williams, W., McGovern, S., Daya, J., Chen, J., Aifuwa, I., Lee, J.S., Fan, R., et al. (2017). Biophysical and biomolecular determination of cellular age in humans. Nat. Biomed. Eng.1, 0093.CrossrefGoogle Scholar

  • Plasschaert, L.W., Žilionis, R., Choo-Wing, R., Savova, V., Knehr, J., Roma, G., Klein, A.M., and Jaffe, A.B. (2018). A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature 560, 377–381.CrossrefPubMedGoogle Scholar

  • Pott, S. (2017). Simultaneous measurement of chromatin accessibility, DNA methylation, and nucleosome phasing in single cells. eLife 6, e23203.CrossrefPubMedGoogle Scholar

  • Ptashne, M. (1986). Gene regulation by proteins acting nearby and at a distance. Nature 322, 697–701.CrossrefGoogle Scholar

  • Raj, A. and van Oudenaarden, A. (2008). Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135, 216–226.CrossrefPubMedGoogle Scholar

  • Rao, C.V., Wolf, D.M., and Arkin, A.P. (2002). Control, exploitation and tolerance of intracellular noise. Nature 420, 231–237.CrossrefPubMedGoogle Scholar

  • Raser, J.M. and O’Shea, E.K. (2004). Control of stochasticity in eukaryotic gene expression. Science 304, 1811–1814.CrossrefPubMedGoogle Scholar

  • Reinius, B. and Sandberg, R. (2015). Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation. Nat. Rev. Genet. 16, 653–664.CrossrefPubMedGoogle Scholar

  • Riera, C.E., Merkwirth, C., De Magalhaes Filho, C.D., and Dillin, A. (2016). Signaling networks determining life span. Annu. Rev. Biochem. 85, 35–64.PubMedCrossrefGoogle Scholar

  • Rivière, I., Sunshine, M.J., and Littman, D.R. (1998). Regulation of IL-4 expression by activation of individual alleles. Immunity 9, 217–228.PubMedCrossrefGoogle Scholar

  • Rogers, K.W. and Schier, A.F. (2011). Morphogen gradients: from generation to interpretation. Annu. Rev. Cell Dev. Biol. 27, 377–407.CrossrefPubMedGoogle Scholar

  • Schoenfelder, S., Sexton, T., Chakalova, L., Cope, N.F., Horton, A., Andrews, S., Kurukuti, S., Mitchell, J.A., Umlauf, D., Dimitrova, D.S., et al. (2010). Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nat. Genet. 42, 53–61.PubMedCrossrefGoogle Scholar

  • Sen, P., Dang, W., Donahue, G., Dai, J., Dorsey, J., Cao, X., Liu, W., Cao, K., Perry, R., Lee, Y.P., et al. (2015). H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev. 29, 1362–1376.PubMedCrossrefGoogle Scholar

  • Simoni, Y., Chng, M.H.Y., Li, S., Fehlings, M., and Newell, E.W. (2018). Mass cytometry: a powerful tool for dissecting the immune landscape. Curr. Opin. Immunol. 51, 187–196.CrossrefGoogle Scholar

  • Stegle, O., Teichmann, S.A., and Marioni, J.C. (2015). Computational and analytical challenges in single-cell transcriptomics. Nat. Rev. Genet. 16, 133–145.PubMedCrossrefGoogle Scholar

  • Strasser, B.J. (2006). A world in one dimension: Linus Pauling, Francis Crick and the central dogma of molecular biology. Hist. Philos. Life Sci. 28, 491–512.Google Scholar

  • Suter, D.M., Molina, N., Gatfield, D., Schneider, K., Schibler, U., and Naef, F. (2011). Mammalian genes are transcribed with widely different bursting kinetics. Science 332, 472–474.PubMedCrossrefGoogle Scholar

  • Swain, P.S., Elowitz, M.B., and Siggia, E.D. (2002). Intrinsic and extrinsic contributions to stochasticity in gene expression. Proc. Natl. Acad. Sci. USA 99, 12795–12800.CrossrefGoogle Scholar

  • Tabbaa, O.P., Nudelman, G., Sealfon, S.C., Hayot, F., and Jayaprakash, C. (2013). Noise propagation through extracellular signaling leads to fluctuations in gene expression. BMC Syst. Biol. 7, 94.PubMedCrossrefGoogle Scholar

  • Todeschini, A.-L., Georges, A., Veitia, R.A. (2014). Transcription factors: specific DNA binding and specific gene regulation. Trends Genet. 30, 211–219.PubMedCrossrefGoogle Scholar

  • Tolhuis, B., Palstra, R.J., Splinter, E., Grosveld, F., and de Laat, W. (2002). Looping and interaction between hypersensitive sites in the active b-globin locus. Mol. Cell 10, 1453–1465.CrossrefGoogle Scholar

  • Trapnell, C. (2015). Defining cell types and states with single-cell genomics. Genome Res. 25, 1491–1498.CrossrefPubMedGoogle Scholar

  • Ucar, D., Marquez, E.J., Chung, C.H., Marches, R., Rossi, R.J., Uyar,A., Wu, T.C., George, J., Stitzel, M.L., Palucka, A.K., et al. (2017). The chromatin accessibility signature of human immune aging stems from CD8+ T cells. J. Exp. Med. 214, 3123–3144.CrossrefPubMedGoogle Scholar

  • Vaquerizas, J.M., Kummerfeld, S.K., Teichmann, S.A., and Luscombe, N.M. (2009). A census of human transcription factors: function, expression and evolution. Nat. Rev. Genet. 10, 252–263.PubMedCrossrefGoogle Scholar

  • Voss, T.C. and Hager, G.L. (2014). Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat. Rev. Genet. 15, 69–81.PubMedCrossrefGoogle Scholar

  • Wagner, A., Regev, A., and Yosef, N. (2016). Revealing the vectors of cellular identity with single-cell genomics. Nat. Biotechnol. 34, 1145–1160.CrossrefPubMedGoogle Scholar

  • Wiley, C.D., Flynn, J.M., Morrissey, C., Lebofsky, R., Shuga, J., Dong, X., Unger, M.A., Vijg, J., Melov, S., Campisi, J. (2017). Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16, 1043–1050.PubMedCrossrefGoogle Scholar

  • Yagi, M., Kishigami, S., Tanaka, A., Semi, K., Mizutani, E., Wakayama, S., Wakayama, T., Yamamoto, T., and Yamada, Y. (2017). Derivation of ground-state female ES cells maintaining gamete-derived DNA methylation. Nature 548, 224–227.PubMedCrossrefGoogle Scholar

  • Ziegenhain, C., Vieth, B., Parekh, S., Hellmann, I., and Enard, W. (2018). Quantitative single-cell transcriptomics. Brief. Funct. Genomics 17, 220–232.CrossrefPubMedGoogle Scholar

About the article

aChrysa Nikopoulou and Swati Parekh: These authors contributed equally to this work.

Received: 2018-11-30

Accepted: 2019-03-27

Published Online: 2019-04-22

Citation Information: Biological Chemistry, 20180449, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2018-0449.

Export Citation

©2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Comments (0)

Please log in or register to comment.
Log in