Biology subjects

Mello, M. F.

Publications and source records attributed to Mello, M. F..

4 recordsLinked to original sources

bioRxiv2026

The compartmental polarization of interphase human chromosomes within the nucleus: A mechanism for transcriptional regulation of large chromosomes

The structure and dynamics of individual chromosomes are significantly modulated by their local environment within the nucleus. It has long been established that heterochromatin (B compartment loci) associates with the lamina meshwork that lines the inner nuclear envelope. However, the extent to which these interactions perturb the chromosomal organization within a territory remains unclear. Using computer simulations and published imaging data, we further characterize the interaction between chromatin and the lamina and find striking consequences of lamina-association on the chromosomal structural ensemble. We find that lamina-associating chromosomes have their compartmentalization polarized in a direction perpendicular to the nuclear surface. Further, lamina-associated chromosomes exhibit shorter average distances between euchromatin loci (A compartment) than chromosomes without lamina contact. Energy landscape analysis of our simulations reveal that the sequestration of heterochromatin to the lamina allows for euchromatin to form more spatial contacts with other segments of euchromatin. The compaction of euchromatin due to lamina-association also diminishes the mobility of these regions. These findings suggest a mechanism for bringing together euchromatic segments that are separated by large genomic distances within a chromosome, potentially to share transcriptional machinery and enhance transcription for large chromosomes, which are often found at the nuclear periphery.

biophysics↗

bioRxiv2026

Asynchronous structural rearrangements govern constriction of the human nuclear pore complex

The nuclear pore complex (NPC) is responsible for transport between the cytoplasm and nucleus. CryoET experiments have resolved multiple conformations of the pore that are dilated or constricted. Since the dilation state will impact transport properties, there is much interest in understanding the energetic factors that regulate dilation/constriction. To this end, we applied a structure-based (G[o]-like) model to study the mechanistic properties of large-scale constriction ( [~] 100[A]) in the human NPC. Even though the structures are symmetric, the simulations implicate asynchronous rear-rangements during constriction. By considering variants of the model, we further characterize the relative contributions of individual proteins to this collective process. Together, this provides an energetic/structural foundation that can guide development of precise physical approaches for studying this elusive motion.

biophysics↗

bioRxiv2024

Compaction-mediated segregation of partly replicated bacterial chromosome

Faithful chromosome segregation during bacterial replication requires global reorganization of the nucleoid, where Structural Maintenance of Chromosomes (SMC) complexes play a crucial role. Here we develop an energy-landscape framework that integrates data-driven pairwise interactions with coarse-grained polymer physics to infer the 3D architectural ensembles of Escherichia coli and Bacillus subtilis chromosomes throughout replication. We show that SMC-mediated long-range lengthwise compaction reshapes the nucleoid to induce a robust mid-replication transition in which the terminus relocates toward the nucleoid center and duplicated origins segregate toward opposite cell halves. SMC-deficient mutants lack this transition and instead exhibit emergent nematic-like alignment of sister chromosomes that impedes segregation. A distinctive inter-sister Hi-C signature accompanies the emergence of the nematic alignment. By systematically tuning nonspecific inter-sister adhesion, we reveal that SMC activity expands the physical regime permitting faithful segregation. This buffering protects segregation against adhesive forces intrinsic to the crowded bacterial nucleoid. Our framework provides mechanistic insight into SMC-dependent co-replication segregation across bacterial species, yielding experimentally testable predictions for imaging and sister-chromosome-resolved Hi-C.

biophysics↗

bioRxiv2019

The Nucleome Data Bank: Web-based Resources to Simulate and Analyze the Three-Dimensional Genome

We introduce the Nucleome Data Bank, a web-based platform to simulate and analyze the three-dimensional organization of genomes. The Nucleome Data Bank enables physics-based simulation of chromosomal structural dynamics through the MEGABASE + MiChroM computational pipeline. The input of the pipeline consists of epigenetic information sourced from the Encode database; the output consists of the trajectories of chromosomal motions that accurately predict Hi-C and FISH data, as well as multiple observations of chromosomal dynamics in vivo. As an intermediate step, users can also generate chromosomal sub-compartment annotations directly from the same epigenetic input, without the use of any DNA-DNA proximity ligation data. Additionally, the Nucleome Data Bank freely hosts both experimental and computational structural genomics data. Besides being able to perform their own genome simulations and download the hosted data, users can also analyze and visualize the same data through custom-designed web-based tools. In particular, the one-dimensional genetic and epigenetic data can be overlaid onto accurate three-dimensional structures of chromosomes, to study the spatial distribution of genetic and epigenetic features. The Nucleome Data Bank aims to be a shared resource to biologists, biophysicists, and all genome scientists. The Nucleome Data Bank (NDB) is available at https://ndb.rice.edu.

bioinformatics↗