Biology subjects

Williams, J. F.

Publications and source records attributed to Williams, J. F..

5 recordsLinked to original sources

bioRxiv2026

Microspatial partitioning of insect-specific viromes and dengue virus transmission risk by Aedes aegypti in Puerto Rico

Mosquito-borne arboviruses remain a major global health threat. Although insect-specific viruses (ISVs) may influence arbovirus transmission across geographic regions, their diversity within Aedes aegypti populations at microspatial scales remains poorly understood. We hypothesized that local environmental variation shapes the A. aegypti core virome, producing distinct ISV profiles in rural and urban populations in Puerto Rico. Metatranscriptomic RNA sequencing of F0 mosquitoes identified thirteen ISVs with habitat-specific virome composition. Partitiviridae was the dominant viral family, while Humaita-Tubiacanga virus (HTV) and Phasi Charoen-like phasivirus (PCLV) exhibited the highest abundance, persistence, and prevalence in urban laboratory colonies. Urban A. aegypti also showed significantly higher dengue virus-1 (DENV-1) infection rates than rural populations, although saliva positivity remained low and did not differ significantly between the two groups. These findings indicate that microspatial ecological variation shapes the A. aegypti virome, but the association of HTV/PCLV with DENV-1 transmission risk is likely multifactorial and nuanced.

microbiology↗

bioRxiv2020

Phase separation enables heterochromatin domains to do mechanical work

The condensation of proteins and nucleic acids underlies the formation of membraneless organelles, which have emerged as major drivers of cellular organization. It remains largely unexplored, however, whether these condensates can impart mechanical function(s) to the cell. The heterochromatin protein HP1- (Swi6 in S. pombe) crosslinks histone H3K9 methylated nucleosomes and has been proposed to undergo condensation to drive the liquid-like clustering of heterochromatin domains. Here we leverage the genetically tractable S. pombe model and a separation-of-function Swi6 allele to elucidate a mechanical function imparted by its condensation. Using a combination of single-molecule imaging, force spectroscopy on individual nuclei, and high-resolution live-cell imaging, we show that Swi6 is critical for nuclear resistance to external force. Strikingly, it is this condensed yet dynamic pool of Swi6, rather than the chromatin-bound molecules, that is essential to imparting mechanical stiffness. Our findings suggest that Swi6 condensates embedded in the chromatin meshwork establish the emergent mechanical behavior of the nucleus as a whole, revealing that biomolecular condensation can influence organelle and cell mechanics.

cell biology↗

bioRxiv2020

Nucleosome-constrained loop extrusion model for the origin of topologically associating domains

The chromosomes - DNA polymers and their binding proteins - are compacted into a spatially organized, yet dynamic, three-dimensional structure. Recent genome-wide chromatin conformation capture experiments reveal a hierarchical organization of the DNA structure that is imposed, at least in part, by looping interactions arising from the activity of loop extrusion factors. The dynamics of chromatin reflects the response of the polymer to a combination of thermal fluctuations and active processes. However, how chromosome structure and enzymes acting on chromatin together define its dynamics remains poorly understood. To gain insight into the structure-dynamics relationship of chromatin, we combine high-precision microscopy in living Schizosaccharomyces pombe cells with systematic genetic perturbations and Rouse- model polymer simulations. We first investigated how the activity of two loop extrusion factors, the cohesin and condensin complexes, influences chromatin dynamics. We observed that deactivating cohesin, or to a lesser extent condensin, increased chromatin mobility, suggesting that loop extrusion constrains rather than agitates chromatin motion. Our corresponding simulations reveal that the introduction of loops is sufficient to explain the constraining activity of loop extrusion factors, highlighting that the conformation adopted by the polymer plays a key role in defining its dynamics. Moreover, we find that the number loops or residence times of loop extrusion factors influences the dynamic behavior of the chromatin polymer. Last, we observe that the activity of the INO80 chromatin remodeler, but not the SWI/SNF or RSC complexes, is critical for ATP-dependent chromatin mobility in fission yeast. Taken together we suggest that thermal and INO80-dependent activities exert forces that drive chromatin fluctuations, which are constrained by the organization of the chromosome into loops.

cell biology↗

bioRxiv2018

Loss of Rap1 supports recombination-based telomere maintenance independent of RNA-DNA hybrids in fission yeast

A subset of cancers rely on telomerase-independent mechanisms to maintain their chromosome ends. The predominant \"alternative lengthening of telomeres\" pathway appears dependent on homology-directed repair (HDR) to maintain telomeric DNA. However, the molecular changes needed for cells to productively engage in telomeric HDR are poorly understood. To gain new insights into this transition, we monitored the state of telomeres during serial culture of fission yeast (Schizosaccharomyces pombe) lacking the telomerase recruitment factor Ccq1. Rad52 is loaded onto critically short telomeres shortly after germination despite continued telomere erosion, suggesting that recruitment of recombination factors is not sufficient to maintain telomeres in the absence of telomerase function. Instead, survivor formation coincides with the derepression of telomeric repeat-containing RNA (TERRA). In this context, degradation of TERRA associated with the telomere in the form of R-loops drives a severe growth crisis, ultimately leading to a novel type of survivor with linear chromosomes and altered cytological telomere characteristics, including the loss of the shelterin component Rap1 (but not the TRF1/TRF2 orthologue, Taz1) from the telomere. We demonstrate that deletion of Rap1 is protective in this context, preventing the growth crisis that is otherwise triggered by degradation of telomeric R-loops in survivors with linear chromosomes. These findings suggest that up-regulation of telomere-engaged TERRA or altered recruitment of shelterin components can support telomerase-independent telomere maintenance.

genetics↗

bioRxiv2018

LEM domain proteins control the efficiency of adaptation through copy number variation

While loss of genome integrity is at the basis of numerous pathologies, including cancer, genome plasticity is necessary to adapt to a changing environment and thus is essential for long-term organismal success. Here we present data supporting a targeted mechanism that promotes adaptation to environmental stress by driving site-specific genome instability tied to transcriptional induction and the formation of RNA-DNA hybrids. Using an in vitro evolution assay we observe that the inner nuclear membrane LEM domain proteins Heh1 and Heh2 play antagonistic roles in inhibiting or promoting adaptation through copy number expansion, respectively, which is also reflected in their genetic interaction networks with genes responsible for transcription-dependent genome instability. Taken together, our data suggest the existence of a LEM domain protein-mediated mechanism by which an immediate transcriptional response to a changing environment drives targeted genome instability to promote increased variation on which selection can act to support long-term adaptation.

genetics↗