Life Sciences Research for Lifelong Health

Karen Lipkow

Research Summary

Research in our lab focuses on the three-dimensional organisation of the eukaryotic genome. We are taking an integrated approach to analyse its structure, individual variability and dynamics. Our analysis is aimed at revealing common rules linking changes in genome organisation to the regulation of gene expression.

We are investigating various aspects of genome architecture using detailed computational models of the nucleus, quantitative fluorescent live cell microscopy, chromatin conformation capture (3C, Hi-C), functional genomics and proteomics.

The questions we are addressing are how does genome structure change over time and in response to external conditions, which are the molecular and biophysical mechanisms responsible for these changes, and which are the biological consequences. We maintain an interest in spatial aspects of signalling in the bacterial chemotaxis system.

Current Publication (pre-press)

Heterogeneous chromatin mobility derived from chromatin states is a determinant of genome organisation in S. cerevisiae.
Sewitz S.A, Fahmi Z., Aljebali L., Bancroft J., Brustolini O.J.B., Saad H., Goiffon I., Varnai C., Wingett S., Wong H., Javierre B.-M., Schoenfelder S., Andrews S., Oliver S.G., Fraser P., Bystricky K., and Lipkow K. (2017)
bioRxiv, 106344. https://doi.org/10.1101/106344

 

Latest Publications

Higher order assembly: folding the chromosome.
Sewitz SA, Fahmi Z, Lipkow K

The linear molecules of DNA that constitute a eukaryotic genome have to be carefully organised within the nucleus to be able to correctly direct gene expression. Microscopy and chromosome capture methods have revealed a hierarchical organisation into territories, domains and subdomains that ensure the accessibility of expressed genes and eventually chromatin loops that serve to bring gene enhancers into proximity of their target promoters. A rapidly growing number of genome-wide datasets and their analyses have given detailed information into the conformation of the entire genome, allowing evolutionary insights, observations of genome rearrangements during development and the identification of new gene-to-disease associations. The field is now progressing into using computational models of genome dynamics to investigate the mechanisms that shape genome structure, placing increasing importance on the role of chromatin associated proteins for this process.

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Current opinion in structural biology, 42, 1879-033X, 162-168, 2017

PMID: 28284913

Systems Biology Approaches for Understanding Genome Architecture.
Sewitz S, Lipkow K

The linear and three-dimensional arrangement and composition of chromatin in eukaryotic genomes underlies the mechanisms directing gene regulation. Understanding this organization requires the integration of many data types and experimental results. Here we describe the approach of integrating genome-wide protein-DNA binding data to determine chromatin states. To investigate spatial aspects of genome organization, we present a detailed description of how to run stochastic simulations of protein movements within a simulated nucleus in 3D. This systems level approach enables the development of novel questions aimed at understanding the basic mechanisms that regulate genome dynamics.

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Methods in molecular biology (Clifton, N.J.), 1431, 1940-6029, 109-26, 2016

PMID: 27283305

An integrated model of transcription factor diffusion shows the importance of intersegmental transfer and quaternary protein structure for target site finding.
Schmidt HG, Sewitz S, Andrews SS, Lipkow K

We present a computational model of transcription factor motion that explains both the observed rapid target finding of transcription factors, and how this motion influences protein and genome structure. Using the Smoldyn software, we modelled transcription factor motion arising from a combination of unrestricted 3D diffusion in the nucleoplasm, sliding along the DNA filament, and transferring directly between filament sections by intersegmental transfer. This presents a fine-grain picture of the way in which transcription factors find their targets two orders of magnitude faster than 3D diffusion alone allows. Eukaryotic genomes contain sections of nucleosome free regions (NFRs) around the promoters; our model shows that the presence and size of these NFRs can be explained as their acting as antennas on which transcription factors slide to reach their targets. Additionally, our model shows that intersegmental transfer may have shaped the quaternary structure of transcription factors: sequence specific DNA binding proteins are unusually enriched in dimers and tetramers, perhaps because these allow intersegmental transfer, which accelerates target site finding. Finally, our model shows that a 'hopping' motion can emerge from 3D diffusion on small scales. This explains the apparently long sliding lengths that have been observed for some DNA binding proteins observed in vitro. Together, these results suggest that transcription factor diffusion dynamics help drive the evolution of protein and genome structure.

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PloS one, 9, 1932-6203, e108575, 2014

PMID: 25333780

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Keywords

chromosome modelling
genome architecture
spatial stochastic simulations
systems biology

Group Members

Latest Publications

Higher order assembly: folding the chromosome.

Sewitz SA, Fahmi Z, Lipkow K

Current opinion in structural biology
42 1879-033X:162-168 (2017)

PMID: 28284913

Systems Biology Approaches for Understanding Genome Architecture.

Sewitz S, Lipkow K

Methods in molecular biology (Clifton, N.J.)
1431 1940-6029:109-26 (2016)

PMID: 27283305

The autoregulation of a eukaryotic DNA transposon.

C Claeys Bouuaert, K Lipkow, SS Andrews

eLife
2 :e00668 (2013)

DOI: 10.7554/eLife.00668

PMID: 23795293

Model for Protein Concentration Gradients in the Cytoplasm.

K Lipkow, DJ Odde

Cellular and molecular bioengineering
1 1:84-92 (2008)

DOI: 10.1007/s12195-008-0008-8

PMID: 21152415

Introducing simulated cellular architecture to the quantitative analysis of fluorescent microscopy.

MA DePristo, L Chang, RD Vale

Progress in biophysics and molecular biology
100 1-3:25-32 (2009)

DOI: 10.1016/j.pbiomolbio.2009.07.002

PMID: 19628003

Amelioration of protein misfolding disease by rapamycin: translation or autophagy?

A Wyttenbach, S Hands, MA King

Autophagy
4 4:542-5 (2008)

PMID: 18418060

The chemotactic behavior of computer-based surrogate bacteria.

D Bray, MD Levin, K Lipkow

Current biology : CB
17 1:12-9 (2007)

DOI: 10.1016/j.cub.2006.11.027

PMID: 17208180

Rapid turnover of stereocilia membrane proteins: evidence from the trafficking and mobility of plasma membrane Ca(2+)-ATPase 2.

M Grati, ME Schneider, K Lipkow

The Journal of neuroscience : the official journal of the Society for Neuroscience
26 23:6386-95 (2006)

DOI: 10.1523/JNEUROSCI.1215-06.2006

PMID: 16763047

Changing cellular location of CheZ predicted by molecular simulations.

Lipkow K

PLoS computational biology
2 1553-7358:e39 (2006)

PMID: 16683020

Simulated diffusion of phosphorylated CheY through the cytoplasm of Escherichia coli.

K Lipkow, SS Andrews, D Bray

Journal of bacteriology
187 1:45-53 (2005)

DOI: 10.1128/JB.187.1.45-53.2005

PMID: 15601687