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Register a new userFrom Hi-C Contact Map to Three-dimensional Organization of Interphase Human Chromosomes
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The probability of two loci, separated by a certain genome length, being in contact can be inferred using the Chromosome Conformation Capture (3C) method and related Hi-C experiments. How to go from the contact map, a matrix listing the mean contact probabilities between a large number of pairs of loci, to an ensemble of three-dimensional structures is an open problem. A solution to this problem, without assuming an assumed energy function, would be the first step in understanding the way nature has solved the packaging of chromosomes in tight cellular spaces. We created a theory, based on polymer physics characteristics of chromosomes and the maximum entropy principles, referred to as HIPPS (Hi-C-Polymer-Physics-Structures) method, that allows us to calculate the 3D structures solely from Hi-C contact maps. We created an ensemble of 3D structures for the 23 chromosomes from lymphoblastoid cells using the measured contact maps as inputs. The HIPPS method shows that conformations of chromosomes are heterogeneous even in a single cell type. The differences in the conformational heterogeneity of the same chromosome in different cell types (normal as well as cancerous cells) can also be quantitatively discerned using our theory. We validate the method by showing that the calculated volumes of the 23 chromosomes from the predicted 3D structures are in good agreement with experimental estimates. Because the method is general, the 3D structures for any species may be calculated directly from the contact map without the need to assume a specific polymer model, as is customarily done.
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In this article, we show how the recent statistical techniques developed in Topological Data Analysis for the Mapper algorithm can be extended and leveraged to formally define and statistically quantify the presence of topological structures coming from biological phenomena in datasets of CCC contact maps.
We investigated the viscoelastic response of model interphase chromosomes by tracking the three-dimensional motion of hundreds of dispersed Brownian particles of sizes ranging from the thickness of the chromatin fiber up to slightly above the mesh size of the chromatin solution. In agreement with previous computational studies on polymer solutions and melts, we found that the large-time behaviour of diffusion coefficient and the experienced viscosity of moving particles as functions of particle size deviate from the traditional Stokes-Einstein relation, and agree with a recent scaling theory of diffusion of non-sticky particles in polymer solutions. Interestingly, we found that at short times large particles are temporary caged by chromatin spatial constraints, which thus form effective domains whose size match remarkably well recent experimental results for micro-tracers inside interphase nuclei. Finally, by employing a known mathematical relation between the time mean-square displacement of tracked particles and the complex shear modulus of the surrounding solution, we calculated the elastic and viscous moduli of interphase chromosomes.
We discuss a polymer model for the 3D organization of human chromosomes. A chromosome is represented by a string of beads, with each bead being colored according to 1D bioinformatic data (e.g., chromatin state, histone modification, GC content). Individual spheres (representing bi- and multi-valent transcription factors) can bind reversibly and selectively to beads with the appropriate color. During molecular dynamics simulations, the factors bind, and the string spontaneously folds into loops, rosettes, and topologically-associating domains (TADs). This organization occurs in the absence of any specified interactions between distant DNA segments, or between transcription factors. A comparison with Hi-C data shows that simulations predict the location of most boundaries between TADs correctly. The model is fitting-free in the sense that it does not use Hi-C data as an input; consequently, one of its strengths is that it can -- in principle -- be used to predict the 3D organization of any region of interest, or whole chromosome, in a given organism, or cell line, in the absence of existing Hi-C data. We discuss how this simple model might be refined to include more transcription factors and binding sites, and to correctly predict contacts between convergent CTCF binding sites.
In this paper we explore relevant electrical properties of two olfactory receptors (ORs), one from rat OR I7 and the other from human OR 17-40, which are of interest for the realization of smell nanobiosensors. The investigation compares existing experiments, coming from electrochemical impedance spectroscopy, with the theoretical expectations obtained from an impedance network protein analogue, recently developed. The changes in the response due to the sensing action of the proteins are correlated with the conformational change undergone by the single protein. The satisfactory agreement between theory and experiments points to a promising development of a new class of nanobiosensors based on the electrical properties of sensing proteins.
Bacteriorhodopsin (bR) is a light-driven proton pump. We use time-resolved crystallography at an X-ray free-electron laser to follow the structural changes in multiphoton-excited bR from 250 femtoseconds to 10 picoseconds. Quantum chemistry and ultrafast spectroscopy allow identifying a sequential two-photon absorption process, leading to excitation of a tryptophan residue flanking the retinal chromophore, as a first manifestation of multi-photon effects. We resolve distinct stages in the structural dynamics of the all-trans retinal in photoexcited bR to a highly twisted 13-cis conformation. Other active site sub-picosecond rearrangements include correlated vibrational motions of the electronically excited retinal chromophore, the surrounding amino acids and water molecules as well as their hydrogen bonding network. These results show that this extended photo-active network forms an electronically and vibrationally coupled system in bR, and most likely in all retinal proteins.
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