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The Interchromatin Compartment Participates in the Structural and Functional Organization of the Cell Nucleus

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The Interchromatin Compartment Participates in the Structural and Functional Organization of the Cell Nucleus The Interchromatin Compartment Participates in the Structural and Functional Organization of the Cell Nucleus Cremer, Thomas; Cremer, Marion; Hübner, Barbara; Silahtaroglu, Asli; Hendzel, Michael; Lanctôt, Christian; Strickfaden, Hilmar; Cremer, Christoph Published in: BioEssays DOI: 10.1002/bies.201900132 Publication date: 2020 Document version Publisher's PDF, also known as Version of record Document license: CC BY-NC Citation for published version (APA): Cremer, T., Cremer, M., Hübner, B., Silahtaroglu, A., Hendzel, M., Lanctôt, C., Strickfaden, H., & Cremer, C. (2020). The Interchromatin Compartment Participates in the Structural and Functional Organization of the Cell Nucleus. BioEssays, 42(2), [1900132]. https://doi.org/10.1002/bies.201900132 Download date: 05. okt.. 2021 PROBLEMS & PARADIGMS Prospects & Overviews www.bioessays-journal.com The Interchromatin Compartment Participates in the Structural and Functional Organization of the Cell Nucleus Thomas Cremer,* Marion Cremer, Barbara Hübner, Asli Silahtaroglu, Michael Hendzel, Christian Lanctôt, Hilmar Strickfaden,* and Christoph Cremer* inseparably connected with their functional This article focuses on the role of the interchromatin compartment (IC) in tasks at all levels, from molecules to genes, shaping nuclear landscapes. The IC is connected with nuclear pore complexes chromatin domains (CDs), chromosome (NPCs) and harbors splicing speckles and nuclear bodies. It is postulated that territories, and the functional nuclear orga- the IC provides routes for imported transcription factors to target sites, for nization at large. The “top-down” approach to explore nu- export routes of mRNA as ribonucleoproteins toward NPCs, as well as for the clear structure and function started in the intranuclear passage of regulatory RNAs from sites of transcription to remote nineteenth century with the discovery of functional sites (IC hypothesis). IC channels are lined by less-compacted the cell nucleus, its indirect division with euchromatin, called the perichromatin region (PR). The PR and IC together the formation of mitotic chromosomes, and [12–14] form the active nuclear compartment (ANC). The ANC is co-aligned with the the first description of chromatin. The inactive nuclear compartment (INC), comprising more compacted “bottom up” followed in the twentieth cen- tury culminating with the discovery that heterochromatin. It is postulated that the INC is accessible for individual chromosomes carry a text written by evolu- transcription factors, but inaccessible for larger macromolecular aggregates tion into immensely long DNA molecules. (limited accessibility hypothesis). This functional nuclear organization The direct visualization of specific genes depends on still unexplored movements of genes and regulatory sequences located on chromosomes became possi- between the two compartments. ble, when Mary Pardue and Joseph Gall invented a method for the molecular hy- bridization of DNA probes to the DNA of cytological preparations.[15] For reviews, see 1. Introduction refs. [16,17]. In 1968, David Comings published a seminal paper about During the last two decades, the compartmentalized structure of “The Rationale for an Ordered Arrangement of Chromatin in the cell nucleus and packaging of its genome has become a key is- the Interphase Nucleus” where he argued for a spaghetti-like sue for the understanding of nuclear functions.[1–8] Methodolog- assembly of chromatin fibers possibly connected to the nuclear ical progress has now reached a state where we are witnessing pore complexes (NPCs).[18,19] During the 1960s and 1970s, the the rise of a new research field, called the 4D nucleome.[9–11] It cell nucleus was still widely conceived as a chemical reaction has become evident that the structural organization of nuclei is vial with proteins and RNAs diffusing in the nuclear sap in a Prof.T.Cremer,Dr.M.Cremer,B.Hübner[+] Prof. A. Silahtaroglu Anthropology and Human Genomics, Department of Biology II Department of Cellular and Molecular Medicine Faculty of Health and Ludwig-Maximilians University (LMU) Medical Sciences Biocenter, Grosshadernerstr. 2, 82152 Martinsried, Germany University of Copenhagen E-mail: [email protected] Nørre Alle 14, Byg.18.03, 2200 Copenhagen N, Denmark Prof. M. Hendzel, Dr. H. Strickfaden Department of Oncology, Cross Cancer Institute University of Alberta The ORCID identification number(s) for the author(s) of this article 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada can be found under https://doi.org/10.1002/bies.201900132 E-mail: [email protected] [+]Present address: Institute of Structural Biology (NISB), School of Bio- Dr.C.Lanctôt logical Sciences, Nanyang Technological University, 50 Nanyang Avenue, Integration Santé Singapore 639798, Singapore 1250 Avenue de la Station local 2-304, Shawinigan, Québec G9N 8K9, Canada © 2020 The Authors. BioEssays published by WILEY Periodicals, Inc. This Prof. C. Cremer is an open access article under the terms of the Creative Commons Institute of Molecular Biology (IMB) Ackermannweg 4, 55128 Mainz, Attribution-NonCommercial License, which permits use, distribution and Germany, and Institute of Pharmacy & Molecular Biotechnology (IPMB) reproduction in any medium, provided the original work is properly cited University Heidelberg and is not used for commercial purposes. Im Neuenheimer Feld 364, 69120 Heidelberg, Germany DOI: 10.1002/bies.201900132 E-mail: [email protected]; [email protected] BioEssays 2020, 42, 1900132 1900132 (1 of 18) © 2020 The Authors. BioEssays published by WILEY Periodicals, Inc. www.advancedsciencenews.com www.bioessays-journal.com largely unrestricted way. Only a few molecular biologists became because of a selective advantage: Inverted rod nuclei act as already interested in problems of 3D genome organization collecting lenses and allow visual orientation in a low-light envi- during the 1970s.[20] Francis Crick, one of the most influential ronment. This example demonstrates the profound potential for advocates of the bottom-up approach, asked “How much does major modifications of nuclear architecture enforced by selective the 3D structure of the eukaryotic genome matter for expression, pressure and also how primarily descriptive top-down strategies compared to the 1D structure?”[21] “The methods of studying 3D pave the way to the identification and further exploration of new structures with precision are far more difficult than the methods mechanisms.[24] available for sequencing DNA. Thus, if it turns out […] that the The discovery of nucleosomes in the 1970s marked the be- 3D structure is not merely a packing device needed mainly for ginning of a major change in our understanding of chromatin’s mitosis but is also of primary importance for gene expression, functional capacities.[25–28] The enigma of the nucleosome’s then […] we will need a more devious and ingenious plan of functional roles beyond DNA packaging was lifted, when it attack. Only time can show which alternative is preferred by was discovered that tightly controlled epigenetic modifications nature and how difficult the problem will turn out to be.” In a contribute directly to regulation of both chromatin structure and lecture delivered in 1977 at the Sixth International Chromosome transcription, prompting a still ongoing change of paradigm in Conference in Helsinki, Crick acknowledged the advance of the our understanding of genetic and environmental interactions. new chromosome banding techniques in genetic mapping and Nucleosomes form ≈10 nm thick chromatin fibers. The fold- the clinical importance to identify all human chromosomes and ing of these fibers into a hierarchy of higher-order chromatin larger deletions and translocations, but reminded his audience structures in nuclei of living cells has remained an intensely of cytogeneticists (one of the authors of this article [T. Cremer] debated problem.[29] At approximately 2 m before (G1) and 4 m was among them): “The metaphase chromosome, which is after DNA replication (G2 and mitosis), the DNA molecules the object of study of many of the conference members, is the contained within a diploid mammalian cell nuclei appear dullest form of chromosome: an inert package needed to make immensely long, given that they are packaged within diploid orderly mitosis possible. […] Unfortunately, this is the least mammalian cell nuclei with typical diameters of between 5 and rewarding form to study microscopically.”[22] Because of the 15 µm. However, packaging a quantity of about 6000 megabase limited resolution of cytological methods, Crick doubted that pairs (Mbp) wrapped around up to 30 million nucleosomes in a they could ever make a meaningful contribution to understand diploid mammalian cell nucleus leaves still plenty of space for the 3D organization of chromosomes. “Evolution, guided by an interchromatin compartment (IC) crowded with non-histone natural selection, must always remain the grandest theme in proteins, RNAs, and functional macromolecular aggregates. biology, but if we are to arrive at a deep understanding […] it is This article emphasizes the perspective that the IC represents a essential (among other things) to know exactly what constitutes nuclear compartment with its own functions which co-evolved a eukaryotic gene.” Crick hoped for possibilities of genetic together with the “crumpled” organization of chromatin.[30] engineering to obtain biochemically useful amounts of a “pure gene,” and ended his lecture with this statement: “I feel
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