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Separate Roles for Chromatin and Lamins in Nuclear Mechanics Nucleus ISSN: 1949-1034 (Print) 1949-1042 (Online) Journal homepage: https://www.tandfonline.com/loi/kncl20 Separate roles for chromatin and lamins in nuclear mechanics Andrew D. Stephens, Edward J. Banigan & John F. Marko To cite this article: Andrew D. Stephens, Edward J. Banigan & John F. Marko (2018) Separate roles for chromatin and lamins in nuclear mechanics, Nucleus, 9:1, 119-124, DOI: 10.1080/19491034.2017.1414118 To link to this article: https://doi.org/10.1080/19491034.2017.1414118 © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group© Andrew D. Stephens, Edward J. Banigan and John F. Marko Accepted author version posted online: 11 Dec 2017. Published online: 28 Dec 2017. Submit your article to this journal Article views: 1662 View related articles View Crossmark data Citing articles: 13 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=kncl20 NUCLEUS 2018, VOL. 9, NO. 1, 119–124 https://doi.org/10.1080/19491034.2017.1414118 EXTRA VIEW Separate roles for chromatin and lamins in nuclear mechanics Andrew D. Stephens a, Edward J. Baniganb,c, and John F. Markoa,b aDepartment of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA; bDepartment of Physics and Astronomy, Northwestern University, Evanston, Illinois, USA; cInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts ABSTRACT ARTICLE HISTORY The cell nucleus houses, protects, and arranges the genome within the cell. Therefore, nuclear Received 31 August 2017 mechanics and morphology are important for dictating gene regulation, and these properties are Revised 29 November 2017 perturbed in many human diseases, such as cancers and progerias. The field of nuclear mechanics Accepted 1 December 2017 has long been dominated by studies of the nuclear lamina, the intermediate filament shell residing KEYWORDS just beneath the nuclear membrane. However, a growing body of work shows that chromatin and chromatin; force; lamin; chromatin-related factors within the nucleus are an essential part of the mechanical response of the micromanipulation; nucleus cell nucleus to forces. Recently, our group demonstrated that chromatin and the lamina provide distinct mechanical contributions to nuclear mechanical response. The lamina is indeed important for robust response to large, whole-nucleus stresses, but chromatin dominates the short-extension response. These findings offer a clarifying perspective on varied nuclear mechanics measurements and observations, and they suggest several new exciting possibilities for understanding nuclear morphology, organization, and mechanics. Introduction measurements, it is important to identify the spatio- The cell nucleus is a mechanically robust and respon- temporal scales probed in each experiment. At the sive structure, and its mechanics are responsible for smallest length scales, isolated S. pombe yeast nuclei protecting the genome and governing gene expression were stretched and compressed by 50–200 nm over sec- through both gene positioning and mechanotransduc- onds via optical tweezers. These experiments revealed tion [1]. There are two major nuclear mechanical that chromatin’s attachment to the nuclear periphery elements - chromatin and lamins. Chromatin is the contributes to nuclear mechanical rigidity on these genome and its associated proteins inside and filling scales [4]. Another small-deformation technique used the nucleus. Lamins are type V intermediate filament magnetic tweezers on beads attached to protein com- proteins that form a polymer network shell at the plexes (nesprin) in the nuclear envelope of mammalian nuclear periphery. Perturbing either of these mechani- nuclei to induce local deformations of 300–600 nm cal components has consequences for both nuclear (5% strain, where strain is defined as the deformation stability and shape. Furthermore, alterations to chro- length as a percentage of the original length of the matin and the lamina occur in many human diseases nucleus) and observed nesprin-dependent mechanical [2,3]. Thus, developing both a conceptual and a quan- adaptation by stiffening over tens of seconds [5]. Others titative understanding of nuclear mechanics is essen- have implemented micropipette aspiration to measure tial to both basic cell nuclear biology and studies of large, instantaneously occurring nuclear strains (150– many human diseases. 500%) and creeping flow over hundreds of seconds on Mechanical response of the cell nucleus has been a portion of the nucleus [6–9]. These experiments sug- probed by a variety of complementary experimental gest a major role for lamin A in determining global techniques. To interpret these various disparate nuclear stiffness. Between these scales, other techniques CONTACT Andrew D. Stephens [email protected] Northwestern University Department of Molecular Biosciences, Pancoe 4211, 2205 Tech Drive, Evanston, IL 60208–3500. Original article: Chromatin and lamin A determine two different mechanical response regimes of the cell nucleus. Stephens, Andrew D., Banigan, Edward J., Adam, Stephen A., Goldman, Robert D., Marko, John F. Molecular Biology of the Cell. 28:1984-1996 (2017). © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 120 A. D. STEPHENS ET AL. provide important insights. Micromanipulation of a pre-calibrated spring constant, see Fig. 1 images). nuclei within cells by a single micropipette revealed a Although we typically isolate nuclei, our experiments role for vimentin and lamins in determining nuclear with nuclei remaining in cells measure a similar force stability [10]. Atomic force microscopy (AFM) experi- response, which suggests that mechanical response of ments have provided compression measurements of the nucleus is dominated by structural components differently sized areas of the nucleus, and have shown that are stable during nuclear isolation [19]. that both chromatin and lamins are major contributors Comparing with other studies, the measured spring to nuclear mechanics [11-14]. constants of 0.1 – 1 nN/mm (and estimated Young’s Each of these experiments provides a unique mea- moduli of 0.2 – 0.5 kPa) in our experiments are within surement and requires a different interpretation the range observed using other nuclear force measure- because each one probes different mechanical attrib- ment techniques (0.1 – 1 kPa, see above). Our tech- utes of the nucleus. These differences arise due to dif- nique produces measurements that lie at the lower ferences in area, magnitude, direction (stretch vs. end of the Young’s modulus range, most likely because compression), and duration of force application. For other force measurements are performed in the pres- example, stretching a small area may only elicit a local ence of the cytoskeleton, have imperfect seals and fluid mechanical response at the nuclear periphery whereas flow (in the case of aspiration), and/or have high larger, whole-nucleus deformation involves all nuclear applied stresses that drive the nucleus to a strongly components. Mechanical measurements may also strain-stiffening response (as explained below). Our depend on whether force is applied to the nucleus via technique therefore presents a new, complementary specific attachments (e.g., to mechanotransducing measure of nuclear mechanics that, as we describe protein complexes such as nesprin [5]) or non-specific below, facilitates and provides a clarification of the rel- interactions (e.g., through micropipette aspiration). ative contributions of chromatin and lamins. Furthermore, these forces can be applied to isolated nuclei or to nuclei in cells with or without an intact Two regimes of nuclear mechanics cytoskeleton, which can further complicate interpreta- tion of measurements. Nonetheless, the majority of A key feature of our experiments is the ability to nuclear force measurements give a Young’s modulus homogeneously stretch at low and high stresses and in the range 0.1 – 1 kPa and 0.1 – 1 nN/mm spring strains across the whole nucleus. This ability provides constants when they can be calculated. The diverse essential information on how the nucleus responds to measurements also indicate that nuclear mechanics forces and deformations of different magnitudes. Spe- are controlled by multiple components. However, they cifically, whole-nucleus extension reveals two approxi- do not specifically identify and measure the distinct mately linear force response regimes with an initial contributions of chromatin and lamins. Recent experi- short-extension regime (Fig. 1, cyan) followed by a ments from our group address this issue. transition to a second, long-extension regime (Fig. 1, To achieve the goal of distinguishing chromatin light red) with a 50% higher stiffness at about 30% and lamin contributions, we developed a new method strain (3 mm, Fig. 1 black line, wild-type [WT]). We that stretches the whole nucleus at physiologically rel- refer to this force-extension behavior as strain stiffen- evant strain rates of 0.01–0.1/s (15–50 nm/s) to typi- ing. The consistency of the presence of these two cally observed strains of 0.1–1(1–10 mm, within
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