Directory
Publications
The last 50 bibliographies
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Space-Scale Hybrid Continuous-Discrete Sliding Frank-Wolfe Method
- Journal : IEEE Signal Processing Letters
- 2024
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Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization.
- Journal : Nat Commun
- 2024
- Although our understanding of the involvement of heterochromatin architecturalfactors in shaping nuclear organization is improving, there is still ongoingdebate regarding the role of active genes in this process. In this study, weutilize publicly-available Micro-C data from mouse embryonic stem cells toinvestigate the relationship between gene transcription and 3D gene folding. Ouranalysis uncovers a nonmonotonic - globally positive - correlation betweenintragenic contact density and Pol II occupancy, independent of cohesin-basedloop extrusion. Through the development of a biophysical model integrating therole of transcription dynamics within a polymer model of chromosome organization,we demonstrate that Pol II-mediated attractive interactions with limited valencybetween transcribed regions yield quantitative predictions consistent withchromosome-conformation-capture and live-imaging experiments. Our work providescompelling evidence that transcriptional activity shapes the 4D genome throughPol II-mediated micro-compartmentalization.
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Mechanism of homology search expansion during recombinational DNA break repair in Saccharomyces cerevisiae.
- Journal : Mol Cell
- 2024
- Homology search is a central step of DNA double-strand break (DSB) repair byhomologous recombination (HR). How it operates in cells remains elusive. Wedeveloped a Hi-C-based methodology to map single-stranded DNA (ssDNA) contactsgenome-wide in S. cerevisiae, which revealed two main homology search phases.Initial search conducted by short Rad51-ssDNA nucleoprotein filaments (NPFs) isconfined in cis by cohesin-mediated chromatin loop folding. Progressive growth ofstiff NPFs enables exploration of distant genomic sites. Long-range resectiondrives this transition from local to genome-wide search by increasing theprobability of assembling extensive NPFs. DSB end-tethering promotes coordinatedsearch by opposite NPFs. Finally, an autonomous genetic element on chromosome IIIengages the NPF, which stimulates homology search in its vicinity. This workreveals the mechanism of the progressive expansion of homology search thatis orchestrated by chromatin organizers, long-range resection,end-tethering, and specialized genetic elements and that exploits the stiff NPFstructure conferred by Rad51 oligomerization.
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A new type of non-Mendelian segregation.
- Journal : Nat Ecol Evol
- 2024
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Mechanism of homology search expansion during recombinational DNA break repair in Saccharomyces cerevisiae
- Journal : Molecular Cell
- 2024
- Homology search is a central step of DNA double-strand break (DSB) repair by homologous recombination (HR). How it operates in cells remains elusive. We developed a Hi-C-based methodology to map single-stranded DNA (ssDNA) contacts genome-wide in S. cerevisiae, which revealed two main homology search phases. Initial search conducted by short Rad51-ssDNA nucleoprotein filaments (NPFs) is confined in cis by cohesin-mediated chromatin loop folding. Progressive growth of stiff NPFs enables exploration of distant genomic sites. Long-range resection drives this transition from local to genome-wide search by increasing the probability of assembling extensive NPFs. DSB end-tethering promotes coordinated search by opposite NPFs. Finally, an autonomous genetic element on chromosome III engages the NPF, which stimulates homology search in its vicinity. This work reveals the mechanism of the progressive expansion of homology search that is orchestrated by chromatin organizers, long-range resection, end-tethering, and specialized genetic elements and that exploits the stiff NPF structure conferred by Rad51 oligomerization.
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The C. elegans SET1 histone methyltransferase SET-2 is not required for transgenerational memory of silencing.
- Journal : MicroPubl Biol
- 2024
- The SET-2 /SET1 histone H3K4 methyltransferase and RNAi pathway components arerequired to maintain fertility across generations in C. elegans . SET-2 preservesthe germline transcriptional program transgenerationally, and RNAi pathways relyon small RNAs to establish and maintain transgenerational gene silencing. Weinvestigated whether the functionality of RNAi-induced transgenerationalsilencing and the composition of pools of endogenous small RNA are affected bythe absence of SET-2 . Our results suggest that defects in RNAi pathways are notresponsible for the transcriptional misregulation observed in the absence ofSET-2 .
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Multiscale simulations reveal TDP-43 molecular-level interactions driving condensation
- Journal : Biophysical Journal
- 2023
- The RNA-binding protein TDP-43 is associated with mRNA processing and transport from the nucleus to the cytoplasm. TDP-43 localizes in the nucleus as well as accumulating in cytoplasmic condensates such as stress granules. Aggregation and formation of amyloid-like fibrils of cytoplasmic TDP-43 are hallmarks of numerous neurodegenerative diseases, most strikingly present in >90% of amyotrophic lateral sclerosis (ALS) patients. If excessive accumulation of cytoplasmic TDP-43 causes, or is caused by, neurodegeneration is presently not known. In this work, we use molecular dynamics simulations at multiple resolutions to explore TDP-43 self- and cross-interaction dynamics. A full-length molecular model of TDP-43, all 414 amino acids, was constructed from select structures of the protein functional domains (N-terminal domain, and two RNA recognition motifs, RRM1 and RRM2) and modeling of disordered connecting loops and the low complexity glycine-rich C-terminus domain. All-atom CHARMM36m simulations of single TDP-43 proteins served as guides to construct a coarse-grained Martini 3 model of TDP-43. The Martini model and a coarser implicit solvent C⍺ model, optimized for disordered proteins, were subsequently used to probe TDP-43 interactions; self-interactions from single-chain full-length TDP-43 simulations, cross-interactions from simulations with two proteins and simulations with assemblies of dozens to hundreds of proteins. Our findings illustrate the utility of different modeling scales for accessing TDP-43 molecular-level interactions and suggest that TDP-43 has numerous interaction preferences or patterns, exhibiting an overall strong, but dynamic, association and driving the formation of biomolecular condensates.
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AlphaFold2 Predicts Whether Proteins Interact Amidst Confounding Structural Compatibility
- Journal : Journal of Chemical Information and Modeling
- 2024
- Predicting whether two proteins physically interact is one of the holy grails of computational biology, galvanized by rapid advancements in deep learning. AlphaFold2, although not developed with this goal, is promising in this respect. Here, I test the prediction capability of AlphaFold2 on a very challenging data set, where proteins are structurally compatible, even when they do not interact. AlphaFold2 achieves high discrimination between interacting and non-interacting proteins, and the cases of misclassifications can either be rescued by revisiting the input sequences or can suggest false positives and negatives in the data set. AlphaFold2 is thus not impaired by the compatibility between protein structures and has the potential to be applied on a large scale.
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Dynamics of Protein–RNA Interfaces Using All-Atom Molecular Dynamics Simulations
- Journal : The Journal of Physical Chemistry B
- 2024
- Facing the current challenges posed by human health diseases requires the understanding of cell machinery at a molecular level. The interplay between proteins and RNA is key for any physiological phenomenon, as well protein–RNA interactions. To understand these interactions, many experimental techniques have been developed, spanning a very wide range of spatial and temporal resolutions. In particular, the knowledge of tridimensional structures of protein–RNA complexes provides structural, mechanical, and dynamical pieces of information essential to understand their functions. To get insights into the dynamics of protein–RNA complexes, we carried out all-atom molecular dynamics simulations in explicit solvent on nine different protein–RNA complexes with different functions and interface size by taking into account the bound and unbound forms. First, we characterized structural changes upon binding and, for the RNA part, the change in the puckering. Second, we extensively analyzed the interfaces, their dynamics and structural properties, and the structural waters involved in the binding, as well as the contacts mediated by them. Based on our analysis, the interfaces rearranged during the simulation time showing alternative and stable residue–residue contacts with respect to the experimental structure.
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Ultrastructure Expansion Microscopy applied to C. elegans embryos.
- Journal : MicroPubl Biol
- 2024
- Visualization of organelles using expansion microscopy has been previouslyapplied to Caenorhadbitis elegans adult gonads or worms. However, its applicationto embryos has remained a challenge due to the protective eggshell barrier. Here,by combining freeze-cracking and ultrastructure expansion microscopy (U-ExM), wedemonstrate a four-time isotropic expansion of C. elegans embryos. As an examplestructure, we chose the nuclear pore and demonstrate that we achieve sufficientresolution to distinguish them individually. Our work provides proof of principlefor U-ExM in C. elegans embryos, which will be applicable for imaging a widerange of cellular structures in this model system.
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