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FEBS Letters 589 (2015) 2931–2943 journal homepage: www.FEBSLetters.org Review The 4D nucleome: Evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments ⇑ Thomas Cremer a, , Marion Cremer a, Barbara Hübner a,1, Hilmar Strickfaden b, Daniel Smeets a, ⇑ ⇑ Jens Popken a, Michael Sterr a,2, Yolanda Markaki a, Karsten Rippe c, , Christoph Cremer d, a Biocenter, Department Biology II, Ludwig Maximilians University (LMU), Martinsried, Germany b University of Alberta, Cross Cancer Institute Dept. of Oncology, Edmonton, AB, Canada c German Cancer Research Center (DKFZ) & BioQuant Center, Research Group Genome Organization & Function, Heidelberg, Germany d Institute of Molecular Biology (IMB), Mainz and Institute of Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Germany article info abstract Article history: Recent methodological advancements in microscopy and DNA sequencing-based methods provide Received 1 April 2015 unprecedented new insights into the spatio-temporal relationships between chromatin and nuclear Revised 19 May 2015 machineries. We discuss a model of the underlying functional nuclear organization derived mostly Accepted 20 May 2015 from electron and super-resolved fluorescence microscopy studies. It is based on two spatially Available online 28 May 2015 co-aligned, active and inactive nuclear compartments (ANC and INC). The INC comprises the com- Edited by Wilhelm Just pact, transcriptionally inactive core of chromatin domain clusters (CDCs). The ANC is formed by the transcriptionally active periphery of CDCs, called the perichromatin region (PR), and the interchromatin compartment (IC). The IC is connected to nuclear pores and serves nuclear import and Keywords: 4D nucleome export functions. The ANC is the major site of RNA synthesis. It is highly enriched in epigenetic Super-resolution fluorescence microscopy marks for transcriptionally competent chromatin and RNA Polymerase II. Marks for silent chro- Electron microscopy matin are enriched in the INC. Multi-scale cross-correlation spectroscopy suggests that nuclear Nuclear architecture architecture resembles a random obstacle network for diffusing proteins. An increased dwell time Active nuclear compartment of proteins and protein complexes within the ANC may help to limit genome scanning by factors or Inactive nuclear compartment factor complexes to DNA exposed within the ANC. Interchromatin compartment Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Perichromatin region Topologically associating domains Hi-C 1. Introduction international 4D Nucleome Workshops, held in Germany (2013) and Japan (2014), have initiated efforts to coordinate this research In this review we describe current progress and perspectives of worldwide [1]. These various initiatives indicate that we are cur- the emerging field of 4D nucleome research. This new term was rently on the verge of a concerted effort to dissect the structure– chosen by the US National Institutes of Health (NIH, USA) as head- function relationships that operate in the cell nucleus. In this ing for a new Common Fund’s program, which was announced in review, we will attempt to integrate published work on nuclear December 2014 with the goal ‘‘to understand the principles behind architecture into a model that may serve as a starting point for the three-dimensional organization of the nucleus in space and upcoming studies within the framework of 4D nucleome programs. time (the 4th dimension), the role nuclear organization plays in To set the stage, a brief historical introduction seems appropri- gene expression and cellular function, and how changes in the ate. The nucleus appeared on the scientific agenda in the early 19th nuclear organization affect normal development as well as various century as a characteristic entity of both plant and animal cells (for diseases.’’ (https://commonfund.nih.gov/4Dnucleome/index). Two review see [2]). Studies performed toward the end of the 19th century and during the beginning of the 20th century culminated in the discovery of the nucleus as the bearer of heredity and in the ⇑ Corresponding authors. Boveri-Sutton chromosome theory of heredity, but this theory E-mail addresses: [email protected] (T. Cremer), Karsten. was severely doubted [3]. According to Rabl (1885) [4] and [email protected] (K. Rippe), [email protected] (C. Cremer). Boveri (1909) [5] interphase chromosomes occupied distinct 1 Present address: Nanyang Technological University, Singapore. regions within a cell nucleus, for which Boveri introduced the term 2 Present address: Helmholtz Center Munich, German Research Center for Environmental Health, Garching, Germany. chromosome territories (CTs). Notably, Boveri was keen to http://dx.doi.org/10.1016/j.febslet.2015.05.037 0014-5793/Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. 2932 T. Cremer et al. / FEBS Letters 589 (2015) 2931–2943 reconcile structural and functional aspects of chromosomes within organization will become an important foundation for the a unified theory of heredity, but lacked the experimental tools to 4D nucleome program to fully understand nuclear structure prove the concept of chromosome territories at his time [3,6].He and function. considered chromosomes as individuals, which retain their iden- (5) The nuclear architecture of rod photoreceptor cells differs tity throughout interphase notwithstanding any possible structural fundamentally in nocturnal and diurnal mammals. The rods transformations. In contrast, contemporary cytologists preferred of diurnal retinas possess the conventional architecture the view that chromosomes would dissolve into chromatin parti- found in nearly all eukaryotic cells, with most heterochrom cles during interphase and that these particles would only aggre- atin situated at the nuclear periphery and euchromatin gate into chromosomes at the onset of the next mitosis. residing toward the nuclear interior. The rods of nocturnal Confronted with this argument, Boveri pointed out that the chro- retinas have a unique inverted pattern, where heterochro- mosome theory of heredity required in such a case that ‘‘all parti- matin localizes in the nuclear center, whereas euchromatin, cles belonging to a given chromosome possess an affinity toward as well as nascent transcripts and splicing machinery, line each other of such a kind that they would come together again in the nuclear border. The inverted pattern forms by remodel- one chromosome’’ at the onset of mitosis [5]. ing of the conventional one during terminal differentiation The rise of molecular biology during the second half of the 20th of rods. The inverted rod nuclei act as collecting lenses, century with its goal to understand mechanisms by which genome and computer simulations indicate that columns of such information is processed was paralleled by a great interest into the nuclei channel light efficiently toward the light-sensing structure of molecular components, such as nucleic acids and pro- rod outer segments [14]. teins. The nucleus was considered as an organell with a complex biochemistry. While great emphasis was laid on the structural elu- The emerging field of 4D nucleome research appreciates that cidation of proteins relevant for nuclear functions, as well as DNA structure–function relationships need to be explored at all levels and nucleosome structure, quantitative studies of higher order of nuclear organization from molecules to the entire system [15]. chromatin arrangements and nuclear organization at large were Notwithstanding the major advancements in nucleome research considered as less important for nuclear functions. Quite fre- during the last few years both with respect to experimental pro- quently they were labeled as ‘only’ descriptive, less rewarding gress and modeling (for reviews see [10,16–25]) we face major and consequently less fundable [7]. It seems that we are currently gaps in our current understanding of how nuclear functions are observing a paradigm change due to the development of advanced interconnected with dynamic changes of nuclear organization. A biophysical and biochemical tools, including the means for the 3D unified theory of the functional nuclear organization with an inter- mapping of entire genomes, as well as advanced microscopic nationally accepted nomenclature is still lacking and appears as a approaches. As pointed out in detail below, the nucleus has major goal of an international nucleome program. Since contribu- emerged as a telling example where changes of higher order chro- tors to FEBS letter special issues are encouraged to express per- matin structure may precede or follow changes of nuclear func- sonal views and provocative ideas, we take advantage of this tions, making nuclear structure and function two inseparable freedom. Our main focus is laid on the space–time organization sides of the same coin. We now have come a full circle from the and functional interplay of the major structural components. We early days, where it was without doubt that understanding the propose an integrative model of functional nuclear organization function of the nucleus with its chromosomes depended essen- based on two co-aligned, active and inactive nuclear compart- tially on understanding higher order chromatin structure. A few ments, abbreviated below as ANC and INC. We review the empiri- recent examples may serve to illustrate this intimate correlation

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