DNA & Chromatin Organisation
Understanding DNA and chromatin organisation inside the cellular nucleus is one of the current big challenges in biology and biophysics. The 3D folding of DNA and chromatin affects the behaviour of genes, while gene activity often determines the compactness and location of genomic regions. We are working on "bottom-up" models to understand this mututal relationship by starting from 1D "epigenetic" information that can be obtained, for instance, via chip-seq experiments. From the 1D pattern of histone modification, our polymer models can reproduce very closely and without fitting the typical 3D folding as captured via "Hi-C" contact maps [o1-o3].
[o1] Brackley et al, Biophys J., 2017 [link]
[o2] Brackley et al, Nucleus, 2017 [link]
[o3] Michieletto, Orlandini and Marenduzzo, Phys Rev X, 2016 [link]
[o4] Brackley et al, Genome Biol., 2016 [link]
Recolourable Polymer Models for Epigenetic Dynamics on Chromatin
All cells in your body have the exact same DNA sequence, and yet a cell in your heart is very different from a cell in your brain! This specialisation (or differentiation) is made possible by "epigenetic" marks which are positioned along DNA in a different way in your heart cells than in your brain. How are epigenetic marks established in the first place on "blank" chromatin and how are these marks remembered by the daughter cells (thereby enabling cell memory) are outstanding question in Biology. In this project we aim to understand the physics behind epignetic memory by modelling chromatin as a polymer whose segments can be dynamically recoloured according to biochemical rules [e1-e3].
See also the Physics Focus on "How cells remember who they are" link to Physics Focus Article
[e1] Michieletto, Orlandini & Marenduzzo, Phys Rev X, 6, 2016 [link]
[e1] Michieletto, Orlandini & Marenduzzo, bioRxiv, 2017 [link]
[e1] Michieletto et al, bioRxiv, 2017 [link]
Unknotted and unlinked ring polymers in the melt behave very differently than their linear counterparts. The reason behind this difference lies in the closed topology of the rings and on the global topological invariance of the system. As a consequence, ring polymers offer a rich variety of behaviours that I am studying through large scale MD simulations. One important aspect that we have discovered is that melts of ring polymers can become glassy when subject to random pinning pertubrations, and this can be explained by threading of ring polymers as forming a spanning network of topological constraints[r1-r4].
[r1] Michieletto et al, MacroLetters, 2014 [link]
[r2] Michieletto & Turner, PNAS, 2016 [link]
[r3] Michieletto, Soft Matter, 2016 [link]
[r4] Michieletto et al, Polymers, 2017 [link]
Knots & Links in Complex Environments
Knots and links are ubiquitous when dealing with long fibers such as polymers or even headphones strings. Nature has found ingenious ways to get rid of knots in the genome of most organisms, through "topological enzymes". On the other hand, there are biological examples in which knots and links are still abundant. One such example is the DNA inside viral capsids: it is so highly knotted that one requires fine techniques such as 2D gel electrophoresis to resolve of the knots. The patterns of these DNA knots form arcs which have been difficult to explain from first principles. In this part of the project we aim to understand topological patterns of knots and links through complex environments such as agarose gels[k1-k2]. Another example is that of the Kinetoplast DNA, which is found in the mitochondrion of some tropical parasites. This is made of thousands of short DNA mini-circles linked in a spanning network resembling a medieval chainmail [k4]. In this part of the project we want to understand how nature has arrived to such complex organisation for this genome and how it can manage to undergo division without incurring into topological problems [k3].
[k1] Michieletto, Marenduzzo, Orlandini, PNAS, 2015 [link]
[k2] Michieletto et al, Soft Matter, 2015 [link]
[k3] Michieletto Orlandini Marenduzzo, Phys. Biol., 2015 [link]