Biology subjects

Amitai, A.

Publications and source records attributed to Amitai, A..

6 recordsLinked to original sources

bioRxiv2020

Viral surface geometry shapes influenza and coronavirus spike evolution

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the glycoprotein (spike). However, not all antigenic sites are targeted equally by antibodies, leading to complex immunodominance patterns. We used 3D computational models to estimate antibody pressure on the seasonal influenza H1N1 and SARS spikes. Analyzing publically available sequences, we show that antibody pressure, through the geometrical organization of spikes on the viral surface, shaped their mutability. Studying the mutability patterns of SARS-CoV-2 and the 2009 H1N1 pandemic spikes, we find that they are not predominantly shaped by antibody pressure. However, for SARS-CoV-2, we find that over time, it acquired mutations at antibody-accessible positions, which could indicate possible escape as define by our model. We offer a geometry-based approach to predict and rank the probability of surface resides of SARS-CoV-2 spike to acquire antibody escaping mutations.

biophysics↗

bioRxiv2019

Telomeric chromosome ends are highly mobile and behave like free double-strand DNA breaks

Chromosome organization and dynamics are critical for DNA transactions, including gene expression, replication, and DNA repair. In yeast, the chromosomes are anchored through their centromeres to the spindle pole body, and their telomeres are grouped into clusters at the nuclear periphery, constraining chromosome mobility. Here, we have used experimental and computational approaches to study the effects of chromosome-nuclear envelope (NE) attachments on the dynamics of S. cerevisiae chromosomes. We found that although centromere proximal loci were, as predicted, more dynamically constrained than distal loci, telomeres were highly mobile, even when positioned at the nuclear periphery. Polymer modeling indicated that polymer ends are intrinsically more mobile than internal sites. We tested this model by measuring the mobility of a double strand break (DSB) end within a chromosome arm. Upon separation of the DSB ends, their mobility significantly increased. Altogether, our results reveal that telomeres behave as highly mobile polymer ends, despite interactions with the nuclear membrane.

cell biology↗

bioRxiv2019

Single particle trajectory statistic to reconstruct chromatin organization and dynamics

Chromatin organization remains complex and far from understood. We discuss here recent statistical methods to extract biophysical parameters from in vivo single particle trajectories of loci to reconstruct chromatin reorganization in response to cellular stress such as DNA damages. We look at the methods to analyze both single loci as well as multiple loci tracked simultaneously and explain how to quantify and describe chromatin motion using a combination of extractable parameters. These parameters can be converted into information about chromatin dynamics and function. Furthermore, we discuss how the time scale of recurrent motion of a locus can be extracted and converted into local chromatin dynamics. We also discuss the effect of various sampling rates on the estimated parameters. Finally, we discuss polymer methods based on cross-linkers that account for minimal loop constraints hidden in tracked loci, that reveal chromatin organization at the 250nm spatial scale. We list and refer to some algorithm packages that are now publicly available. To conclude, chromatin organization and dynamics at hundreds of nanometers can be reconstructed from locus trajectories and predicted based on polymer models.

genomics↗

bioRxiv2018

Local decondensation at double-stranded DNA breaks modifies chromatin at long distances and reduces encounter times during homology search

Double-strand break (DSB) repair by homologous recombination (HR) requires an efficient and timely search for a homologous template. Here we first study global chromatin re-organization following a single DSB: due to the potential release of cross-linkers such as cohesin and CTCF molecules near the DSB site, loops are released and chromatin is decondensed, explaining the change of chromatin locus motion at larger genomic distances. This mechanism provides an elementary explanation for the increase of the anomalous exponent at sites located far away from the DSB, after break induction. Second, we explore the consequences of chromatin reorganization for the homology search during DNA repair: using polymer models, we estimate the mean first encounter time (MFET) between two loci on the chromatin in a confined nucleus. Reducing tethering forces, as reported experimentally on chromatin, is associated with a local de-condensation near the break followed by the extrusion of the breaks. Consequently, we report here that the mean first encounter time between homologous sites is decreased by two orders of magnitude even when the homologue sequence is located on the nuclear boundary. To conclude, our results suggest that local changes in inter-nucleosomal contacts near DSBs, by cohesin removal, remodel the chromatin and drastically shorten the time required to complete a long-range search for a homologous template.

genetics↗

bioRxiv2018

Guided nuclear exploration increases CTCF target search efficiency

Mammalian genomes are enormous. For a DNA-binding protein, this means that the number of non-specific, off-target sites vastly exceeds the number of specific, cognate sites. How mammalian DNA-binding proteins overcome this challenge to efficiently locate their target sites is not known. Here through live-cell single-molecule tracking, we show that CCCTC-binding factor, CTCF, is repeatedly trapped in small zones in the nucleus in a manner that is largely dependent on its RNA-binding region (RBR). Integrating theory, we devise a new model, Anisotropic Diffusion through transient Trapping in Zones (ADTZ), to explain this. Functionally, transient RBR-mediated trapping increases the efficiency of CTCF target search by [~]2.5 fold. Since the RBR-domain also mediates CTCF clustering, our results suggest a \"guided\" mechanism where CTCF clusters concentrate diffusing CTCF proteins near cognate binding sites, thus increasing the local ON-rate. We suggest that local \"guiding\" may represent a general target search mechanism in mammalian cells.

biophysics↗

bioRxiv2018

Chromatin configuration affects the dynamics and distribution of a transiently interacting protein

The interaction of proteins with chromatin regulates many cellular functions. Most DNA-binding proteins interact both non-specifically and transiently [1] with many chromatin sites as well as specifically and more stably with cognate binding sites. These interactions and chromatin structure are important in governing protein dynamics [2, 3]. However, the effect of these transient interactions on protein motion and distribution has yet been shown from a first principle.\n\nSome aspects of protein interactions with DNA have been studied in the context of the search of a gene promoter site by a transcription factor (TF) [4]. It was first noted [5] that the search for a promoter site by a TF would be faster if it involves 3d excursions, as well as sliding of the protein along DNA [6], as was shown in prokaryotes [7]. These different types of motion were observed ex ...

biophysics↗