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About the Mechanobiology Institute, National University of Singapore

About MBIOne of four Research Centres of Excellence at NUS, MBI is working to identify, measure and describe how the forces for motility and morphogenesis are expressed at the molecular, cellular and tissue level.
GV Shivashankar 2017-05-23T17:59:58+00:00
GV SHIVASHANKAR

GV SHIVASHANKAR

Deputy Director, Mechanobiology Institute, IFOM-NUS Chair Professor, National University of Singapore

shiva.gvs@gmail.com
+65 6516 2712 ext 62712
Level 10 T-Lab
National University of Singapore
5A Engineering Drive 1
Singapore 117411

Curriculum Vitae

Laboratory website
Nuclear Mechanics & Genome Regulation Laboratory

IFOM GV Shivashankar Lab

Research Program
Molecular Mechanics of Mechanotransduction Group

Affiliations

Head, IFOM-NUS Joint Research Laboratory, National University of Singapore

Recent Research

Signaling in 3D

MBI Scientists reveal a spatial dimension to cell signaling

GV Shivashankar

Deputy Director and Principal Investigator

Research Areas

Nuclear mechanics and genome regulation

Nuclear Mechanics & Genome Regulation Laboratory

Shivashankar’s lab pursues research in understanding the role of cell geometry on nuclear mechanics and genome regulation.

Cells, under physiological conditions, acquire a number of well-defined morphologies. Alterations in their shape, by mechanical microenvironment and/or cytokine signals, have profound impact on tissue homeostasis. While cells undergo changes in shape, for example, during circulation, crawling, extrusion or transmigration; the extent and duration to which such shape changes occur would have critical roles in regulating nuclear function including gene expression. In this context, how cell shape modulation alters nuclear mechanical architecture and how it integrates with the 3D organization of chromosomes and transcription networks are rather unexplored. Understanding the biophysical design principles underlying such processes will have important implications in establishing mechano-chemical routes to cellular reprogramming and in developing biomarkers for early disease diagnosis.

Centered on this theme, our ongoing studies are beginning to provide a quantitative framework to explore the coupling between cell geometry and genome regulation. For these studies, we employ a multidisciplinary approach combining microfabrication techniques to sculpt single cell geometry, high-resolution microscopy, genomics and theoretical modelling.

Current Projects

Maximum intensity projection of confocal images of phalloidin (green), microtubule antibody (red) and Hoechst (blue) stainings in a NIH3T3 fibroblast cultured on 1800µm2 circle fibronectin pattern.

Maximum intensity projection of confocal images of phalloidin (green), microtubule antibody (red) and Hoechst (blue) stainings in a NIH3T3 fibroblast cultured on 1800µm2 circle fibronectin pattern.

Role of cell-geometry on nuclear and chromatin plasticity

Recent studies, including work from our own laboratory, have shown that changes in cell geometry leads to alterations in actin cytoskeletal architecture. This in turn modulates nuclear morphology via the physical links on the nuclear envelope and the lamin meshwork. However the role of cell shape regulated dynamic alterations in the cytoskeleton, on nuclear and chromatin plasticity is less understood. To address this, we use fibronectin coated micropatterns to define cell geometries with distinct cytoskeletal architecture and directly visualize the alterations in nuclear and chromatin dynamics using high resolution quantitative microscopy. The projects include probing the role of cell geometry on i) chromatin (heterochromatin and telomere) plasticity ii) its role in nuclear reprogramming.

Image of a mouse fibroblast cell seeded on a fibronectin coated small circular substrate showing Chr2 (Red), Chr6 (green), and DNA (Blue). Scale bar: 5um

Image of a mouse fibroblast cell seeded on a fibronectin coated small circular substrate showing Chr2 (Red), Chr6 (green), and DNA (Blue). Scale bar: 5um

Defining a nuclear mechanical code for genome regulation

Modulation in cell geometric constraints has been shown to result in changes gene expression patterns. However, the critical role of 3D organization of the nuclear architecture and chromosome assembly in facilitating this genome regulation is unclear. To address this, we systematically alter fibroblast cell geometry and map whole genome transcriptome using microarray analysis. In addition we map chromosome positions using in situ hybridization techniques and directly visualize specific chromosome contacts under different geometric constraints using super-resolution microscopy. We are currently exploring i) transcription dependent reorganization of chromosome positions and functional gene clusters with altered cell-geometry ii) lamin A/C dependent active mechanisms underlying such chromosome reorganization.

shiva-interior-3-mechanotransductionMatrix and cytokine assisted nuclear mechanotransduction

Recent studies have shown that, mechanical constraints in conjunction with soluble cytokine signals alter cellular behavior within the local tissue microenvironment. However the mechanisms underlying the interplay between these signals in regulating gene expression and thus cell behavior at the single-cell resolution are unexplored.

A number of diseases, including fibrosis and cancer, originate at the single-cell level within the tissue microenvironment and therefore a quantitative understanding of the modular codes underlying these processes would be essential to develop therapeutic models. In these projects we study i) matrix and cytokine induced nuclear mechanotransduction ii) its role in chromosome contact maps and gene expression.

The dynamics of Nucleus (H2B-GFP labelled) in NIH cells constrained to circular geometry

The dynamics of Nucleus (H2B-GFP labelled) in NIH cells constrained to circular geometry

Nuclear microrheology and single-cell disease diagnostics

Cell-geometric constraints have profound impact on cytoskeletal organization thus influencing nuclear positioning and its microrhelogical response. For this, a number of cytoskeletal-to-nuclear linking proteins have been shown to be critical in regulating nuclear homeostatic balance. Quantitative analysis of these alterations could potentially serve as quantitative physical biomarkers of various diseases including cancer. Based on this, we are developing miniaturized single-cell assays systems to define novel paradigms in early diagnostics. In these projects we study i) impact of cell geometry on nuclear positioning and its microrhelogy ii) implementing high-content and high-throughput nuclear biomechanical disease diagnostic device platforms.

Biography

Prof GV Shivashankar is currently the Deputy Director of Mechanobiology Institute, National University of Singapore. Shivashankar’s laboratory is focused on understanding the role of cell geometry on nuclear mechanics and genome regulation in living cells using a multi-disciplinary approach. He carried out his PhD research at the Rockefeller University (1994-1999) and Postdoctoral research at NEC Research Institute, Princeton USA (1999-2000). He started his laboratory at the National Center for Biological Sciences, TIFR- Bangalore, India (2000-2009) before relocating to a tenured faculty position at the National University of Singapore in 2009. His scientific awards include; the Birla Science Prize (2006), The Swarnajayanthi Fellowship (2007) and was elected to the Indian Academy of Sciences (2010). He Edited the Methods in Cell Biology series book on “Nuclear Mechanics and Genome Regulation” (2010), Elsevier Press. More recently he also Heads the Joint Research Laboratory with FIRC Institute of Molecular Oncology (IFOM), Milan, Italy and was appointed as an IFOM-NUS Chair Professor in 2014.

Education

PhD The Rockefeller University, USA

Funding

Mechanobiology Institute, Ministry of Education Tier-3 Co-Investigator Grant & IFOM-MBI Joint Research Laboratory, Singapore.

Recent Publications

  1. Radhakrishnan AV, Jokhun DS, Venkatachalapathy S, and Shivashankar GV. Nuclear Positioning and Its Translational Dynamics Are Regulated by Cell Geometry. Biophys. J. 2017; 112(9):1920-1928. [PMID: 28494962]
  2. Jagielska A, Lowe AL, Makhija E, Wroblewska L, Guck J, Franklin RJM, Shivashankar GV, and Van Vliet KJ. Mechanical Strain Promotes Oligodendrocyte Differentiation by Global Changes of Gene Expression. Front Cell Neurosci 2017; 11:93. [PMID: 28473753]
  3. Mitra A, Venkatachalapathy S, Ratna P, Wang Y, Jokhun DS, and Shivashankar GV. Cell geometry dictates TNFα-induced genome response. Proc. Natl. Acad. Sci. U.S.A. 2017;. [PMID: 28461498]
  4. Kumar A, and Shivashankar GV. Dynamic interaction between actin and nesprin2 maintain the cell nucleus in a prestressed state. Methods Appl Fluoresc 2016; 4(4):044008. [PMID: 28192301]
  5. Wang Y, Ratna P, and Shivashankar GV. Superresolution imaging of nanoscale chromosome contacts. Sci Rep 2017; 7:42422. [PMID: 28186153]
  6. Ruprecht V, Monzo P, Ravasio A, Yue Z, Makhija E, Strale PO, Gauthier N, Shivashankar GV, Studer V, Albiges-Rizo C, and Viasnoff V. How cells respond to environmental cues - insights from bio-functionalized substrates. J. Cell. Sci. 2016;. [PMID: 27856508]
  7. Nakazawa N, Sathe AR, Shivashankar GV, and Sheetz MP. Matrix mechanics controls FHL2 movement to the nucleus to activate p21 expression. Proc. Natl. Acad. Sci. U.S.A. 2016;. [PMID: 27742790]
  8. Uhler C, and Shivashankar GV. Geometric Control and Modeling of Genome Reprogramming. Bioarchitecture 2016;. [PMID: 27434579]
  9. Sathe AR, Shivashankar GV, and Sheetz MP. Nuclear transport of paxillin depends on focal adhesion dynamics and FAT domains. J. Cell. Sci. 2016; 129(10):1981-8. [PMID: 27068537]
  10. Maharana S, Iyer KV, Jain N, Nagarajan M, Wang Y, and Shivashankar GV. Chromosome intermingling-the physical basis of chromosome organization in differentiated cells. Nucleic Acids Res. 2016; 44(11):5148-60. [PMID: 26939888]

Lab Members

Saradha Venkatachalapathy

May 24th, 2017|Comments Off on Saradha Venkatachalapathy

PhD Student, Shivashankar Group

Aninda Mitra

May 19th, 2017|Comments Off on Aninda Mitra

Research Fellow IFOM, Visiting Research Fellow MBI, Shivashankar Group

Karthik Damodaran

Mar 30th, 2017|Comments Off on Karthik Damodaran

PhD Student, Shivashankar Group

Jean-Francois Rupprecht

Mar 30th, 2017|Comments Off on Jean-Francois Rupprecht

Research Fellow, Shivashankar Group, Prost Group

Aradhana Bharti

Mar 30th, 2017|Comments Off on Aradhana Bharti

Research Assistant, Shivashankar Group

Bibhas Roy

Mar 30th, 2017|Comments Off on Bibhas Roy

Research Fellow IFOM, Visiting Research Fellow MBI, Shivashankar Group

Mallika Nagarajan

Mar 30th, 2017|Comments Off on Mallika Nagarajan

Research Associate, Shivashankar Group

Jokhun Doorgesh Sharma

Mar 23rd, 2017|Comments Off on Jokhun Doorgesh Sharma

PhD Student, Shivashankar Group

Wang Yejun

Mar 23rd, 2017|Comments Off on Wang Yejun

Research Assistant, Shivashankar Group

Shang Yuqing

Mar 23rd, 2017|Comments Off on Shang Yuqing

Research Associate, Shivashankar Group