DNA Recombination and Retroviral IntegrationRetroviral infection is a process through which a virus injects its genetic material (RNA) into a host cell. The RNA is then retro-transcribed into DNA, which is then "integrated" into the host genome. The most famous example of retrovirus is HIV. The way in which HIV and other retroviruses infect the host is still an open problem. Intriguingly, the DNA of retroviruses is frequently found in specific regions of genomes called "hot-spots" which display highly non-random distributions. The process underlying this non-random integration site selection has been subject of decades of intense research and debate. Most of this phenomenology is reported as empirical observations and attributed to the action of proteins, such as chaperones. At the same time, the integration of HIV and other viral DNA into the host is a topological problem, in that it requires a reconnection operation to be performed in order to permanently insert the viral genetic material (topologically equivalent to a circle) into host chromosomes (topologically equivalent to a line).
[re1] Michieletto et al, Nature Communications, 2019
DNA and 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 [o0-o6].
[o6] Michieletto et al, NAR, 2018
[o5] Brackley et al, Biophys J., 2017
[o4] Brackley et al, NAR, 2016
[o3] Brackley et al, Nucleus, 2016
[o2] Michieletto, Orlandini and Marenduzzo, Phys Rev X, 2016
[o1] Brackley et al, Genome Biol., 2016
[o0] Brackley et al, PNAS, 2013
Recolourable Polymer Models for Chromatin with Dynamic EpigenomeAll 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 cells after division are outstanding question in Biology. In this project we aim to understand the interplay between 1D epignetic information and 3D chromatin organisation in order to shed light into epigenetic memory and cellular fate. [e1-e3].
See also the Physics Focus on "How cells remember who they are"
[e3] Michieletto et al, NAR, 2017
[e2] Michieletto, Orlandini and Marenduzzo, Sci. Rep., 2017
[e1] Michieletto, Orlandini and Marenduzzo, Phys Rev X, 6, 2016
Ring PolymersUnknotted 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
[r2] Michieletto and Turner, PNAS, 2016
[r3] Michieletto, Soft Matter, 2016
[r4] Michieletto et al, Polymers, 2017
Knots and Links in Complex EnvironmentsKnots 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 identify all the possible knots. An example of abundatly linked structures can be found in the mitochondrion of flagellated protists of the class Kinetoplastida, which displays an arrangement aking to that of a "medieval chainmail" [k1]. In this project we aim to understand the behaviour of knots and links when moving through complex environments such as agarose gels [k2-k3] and, at the same time, we also try to shed light into topologically complex systems such as that of the Kinetoplast DNA.
[k3] Michieletto, Marenduzzo, Orlandini, PNAS, 2015
[k2] Michieletto et al, Soft Matter, 2015
[k1] Michieletto Orlandini Marenduzzo, Phys. Biol., 2015