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Chromatin Biochemistry and Biophysics



DESCRIPTION OF LAB RESEARCH WORK

 
Fig. 1.
Structure of the 2.2 Å-resolution telomeric NCP.(a) Telo-NCP structure (b) Base steps between SHL −2.5 to SHL 2.5 at the minor groove pressure points in Telo-NCP. (c) Comparison of the positioning of the telomeric DNA, α-satellite, 601 and 601L DNA on the histone octamer. (d) The stretching (red) on the telomeric NCP between SHL 4.5 to 5. (e) Stretching (red) on the telomeric NCP between SHL −4.5 to −5. (Soman et al, NAR, 48(10), 5383–5396, 2020)
  Fig. 2.
DNA phase separation with formation of hexagonally ordered DNA liquid crystals (A and B) and DNA toroid (C and D.) Results from bottom-up multiscale computer simulations using the Inverse Monte Carlo method. (Sun et al, NAR, 47(11), 5550-5562, 2019)


Human telomeres constitute the protective structure at the end of the chromosomes with repetitive TTAGGG sequences that are about 10kbp. Little is known about the consequences of this unique sequence for chromatin structural and dynamic properties. Although it is established that telomeric DNA is packaged in chromatin with an unusually short (157 bp) nucleosome repeat length (NRL) and can form nucleosomes and chromatin, almost nothing is known about the telomeric nucleosome core and telomeric chromatin structure at the detailed molecular level.

A general aim of our research is the unravelling of the principles and control of the packaging of DNA in the cell nucleus within the context of chromatin with emphasis to the unique telomeric chromatin. We are interested in understanding the molecular interactions and the (electrostatic) mechanisms that induce, stabilize and regulate chromatin folding and what are the implications of this for gene regulation

LAB MEMBERS
LEAD PI
Lars Nordenskiöld
Chair, School of Biological Sciences
Professor, School of Biological Sciences

Email: larsnor@ntu.edu.sg
Phone: (65) 6592 7506
Office:SBS-01N-01
Nikolay Korolev
Principal Research Fellow

Email: korolev@ntu.edu.sg
Chen Qinming
Research Fellow

Email: qmchen@ntu.edu.sg
Sun Tiedong
Research Fellow

Email: tdsun@staff.main.ntu.edu.sg
Aghil Soman
Research Assistant

Email: asoman@ntu.edu.sg
Chinmayi Prasanna
Ph.D student

Email: chinmayi003@e.ntu.edu.sg
Vishal Minhas
Ph.D student

Email: minh0006@e.ntu.edu.sg
Wong Sook Yi
Ph.D student

Email: wong1010@e.ntu.edu.sg


CURRENT PROJECTS
Some specific aims are:
  • To experimentally and theoretically investigate the folding of recombinant in vitro prepared nucleosome core particles (NCP) and well-defined chromatin in the form of nucleosome arrays and how this is affected by changes of the histone tail modifications and transcription factor binding with applications to telomeric chromatin.

  • To identify the difference in structure and dynamics between telomeric and “normal” canonical nucleosomes and chromatin, using biophysical and structural methods like X-ray crystallography, EM and solid-state NMR (Fig. 2).

  • To characterise the binding and structural and dynamic properties of HP1 interaction with telomeric chromatin and compare it with canonical chromatin

  • To establish the physical basis in terms of electrostatic/molecular interactions for DNA and chromatin phase separations (LLPS), it’s structure and dynamics using computer modelling tools.

These aims are realized by using a combination of molecular biology, biochemical and chemical synthesis techniques in combination with biophysical approaches such as single molecule measurements (magnetic tweezers), solid-state NMR, X-ray structure determination, synchrotron x-ray diffraction (SAXS), analytical ultracentrifugation, as well as well as Cry-Electron Microscopy (EM) methods. Experimental work is often performed in combination with our computer modelling studies.

Subprojects:
  • Telomeric chromatin: Unravelling the structural properties of the telomeric nucleosome and chromatin and how it differs from canonical chromatin.
  • Understanding the structural and dynamic properties of condensed heterochromatin within the context of telomeres. Specifically, the role of heterochromatin protein 1 (HP1) by solid-state NMR study of heterochromatin maintenance by HP1 protein at telomeres
  • Multi-scale computer modeling of electrostatic interactions in DNA, the nucleosome core particle (NCP), chromatin up to mesoscale megabase size chromosomal chromatin for an understanding of chromatin liquid liquid phase separation (LLPS).

PUBLICATIONS
  • Aghil Soman, Chong Wai Liew, Hsiang Ling Teo, Nikolay Berezhnoy, Vincent Olieric, Nikolay Korolev, Daniela Rhodes, Lars Nordenskiöld, The Human Telomeric Nucleosome Displays Distinct Structural and Dynamic Properties, Nucleic Acids Research, 48(10), 5383–5396, 2020

  • Anatoly Zinchenko, Qinming Chen, Nikolay Berezhnoy, Sai Wang, Lars Nordenskiöld, Compaction and Self-Association of Megabase-Sized Chromatin is Induced by Anionic Protein Crowding, Soft Matter, 2020, 16, 4341-4341

  • Vishal Minhas, Tiedong Sun, Alexander Mirzoev, Nikolay Korolev, Alexander P. Lyubartsev and Lars Nordenskiöld, “Modeling DNA Flexibility: Comparison of Force Fields from Atomistic to Multiscale Levels”, J. Phys. Chem. B, 2020, 124, 1, 38–49

  • Tiedong Sun, Alexander Mirzoev, Vishal Minhas, Nikolay Korolev, Alexander P. Lyubartsev and Lars Nordenskiöld, “A multiscale analysis of DNA phase separation: from atomistic to mesoscale level”, Nucleic Acids Research, 47(11), 5550-5562, 2019

  • Xiangyan Shi, Chinmayi Prasanna, Toshio Nagashima, Toshio Yamazaki, Konstantin Pervushin and Lars Nordenskiöld, Structure and Dynamics in the Nucleosome Revealed by Solid-State NMR, Angewandte Chemie, Int. Ed., 57,9734 –9738, 2018

  • Nikolay Korolev#, Alexander P. Lyubartsev and Lars Nordenskiöld “A systematic analysis of nucleosome core particle and nucleosome-nucleosome stacking structure”, Scientific Reports, 8:1543, |DOI:10.1038/s41598-018-19875-0, 2018

  • Anatoly Zinchenko, Nikolay Berezhnoy, William Rosencrans, Nikolay Korolev, Johan RC van der Maarel and Lars Nordenskiöld, “Single-Molecule Compaction of Megabase-Long Chromatin Molecules by Multivalent Cations”, Nucleic Acids Research, 46(2) 635–649, 2018

  • Qinming Chen, Renliang Yang, Nikolay Korolev, Chuan Fa Liu and Lars Nordenskiöld, Regulation of Nucleosome Stacking and Chromatin Compaction by the Histone H4 N-Terminal Tail - H2A Acidic Patch Interaction, Journal of Molecular Biology, 429(13), 2075-2092, 2017

  • Ying Liu, Chenning Lu, Ye Yang, Yanping Fan, Renliang Yang, Chuan Fa Liu, Nikolay Korolev, and Lars Nordenskiöld; “Influence of Histone Tails and H4 Tail Acetylations on Nucleosome–Nucleosome Interactions”, Journal of Molecular Biology, 414, 749–764, 2011

  • Abdollah Allahverdi, Yang Renliang, Nikolay Korolev, Yanping Fan, Curt Davey, Chuan Fa Liu and Lars Nordenskiöld, “The effects of histone H4 tail acetylations on cation-induced chromatin folding and self-association”, Nucleic Acids Research, 39(5): 1680-1691, 2011
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