Biology subjects

Jevtic, P.

Publications and source records attributed to Jevtic, P..

6 recordsLinked to original sources

bioRxiv2026

Systemic degradation of repressive transcription factors gates gene expression and cell fate specification

While proteasomes are best known for eliminating defective proteins or turning off signaling pathways, they also enable crucial cellular activities. Critical among these, proteasomes allow cells to initiate gene expression, but underlying targets and regulatory mechanisms remain poorly understood. Here, we report that proteasomes drive the systemic degradation of repressive trans-cription factors to eject TLE/Groucho-family co-repressors from chromatin and thereby constantly free transcription start sites for activator binding. This circuitry requires the E3 ligase SCFFBXL14, which modifies its targets dependent on presentation by TLEs, but independently of their identity. The continuous cycling of co-repressors off chromatin, as achieved by systemic turnover of a protein family, is essential for stem cells to translate developmental cues into lineage-specific gene expression, and it is disrupted by cancer mutations in TLE1 that impair SCFFBXL14-recruit-ment. We conclude that systemic degradation of repressive transcription factors establishes co-repressor dynamics required for genes expression and cell fate specification.

biochemistry↗

bioRxiv2026

Predicting Valley Fever Outbreaks: Novel Mechanistic Models Incorporating Climate and Ecological Interactions

Coccidioidomycosis (Valley fever) is an environmentally acquired fungal infection endemic to the arid Americas, presenting a growing public health challenge as changing environmental patterns threaten to amplify exposure risks across both established and newly recognized endemic zones. Historically, forecasting efforts have relied on statistical correlations with meteorological variables. These phenomenological models often fail to capture the complex, non-linear interactions between the saprobic (environmental) and parasitic (host) life cycles of Coccidioides, particularly under non-stationary climate conditions. Here, we present a hierarchy of mechanistic Ordinary Differential Equation (ODE) models that explicitly map environmental drivers to the distinct biological stages of the fungal life cycle. We developed successive model iterations, incrementally incorporating soil moisture retention, temperature-dependent growth rates, and wildlife reservoir dynamics, and calibrated them against human case data from various regions of Arizona. We derive a time-variant environmental reproduction number and test how transmission potential fluctuates dynamically with environmental forcing. The comparative forecasting analysis, utilizing various statistical tests, information criteria, Relative Root Mean Square Error, the Diebold-Mariano test, and the Modified Diebold-Mariano, shows how the models progress. Mechanistic models based solely on continuous fungal growth perform worse than statistical baselines. By integrating climate data, we increase predictive power to a level comparable to that of the statistical model. Explicitly incorporating a wildlife reservoir as a biological amplifier significantly improves model forecasting over statistical baselines. This framework offers public health officials a biologically grounded tool to predict disease burden and guide targeted interventions responding to changing climate patterns.

ecology↗

bioRxiv2025

Translation-driven temporal control for intertwined protein assembly

Protein complexes are essential to cells. However, how structurally intertwined protein subunits can assemble faithfully is poorly understood. Here, we reveal a "temporal control" mechanism driven by coupled ribosomes to form intertwined dimers. Using Disome Selective Profiling and optical tweezers, we show that the BTB domains of KEAP1, KLHL12, and PATZ1 form stable closed states as monomers, thus impeding proposed domain-swapping assembly routes. By contrast, the timed emergence of nascent chain segments during translation enables alternative folding-assembly pathways that bypass the closed monomeric state. Analysis indicates that this mechanism works in concert with dimerization quality control by the E3 ligase SCF-FBXL17, and is relevant across the BTB domain family. This study shows that ribosome cooperation expands the range of possible protein architectures.

molecular biology↗

bioRxiv2022

Identification of epigenetic modulators as determinants of nuclear size and shape

The shape and size of the human cell nucleus is highly variable amongst cell types and tissues. Changes in nuclear morphology are associated with disease, including cancer, as well as with premature and normal aging. Despite the very fundamental nature of nuclear morphology, the cellular factors that determine nuclear shape and size are not well understood. To identify regulators of nuclear architecture in a systematic and unbiased fashion, we performed a high-throughput imaging-based siRNA screen targeting 867 nuclear proteins including chromatin-associated proteins, epigenetic regulators, and nuclear envelope components. Using multiple morphometric parameters, we identified cell-type specific and general effectors of nuclear size and shape. Interestingly, most identified factors altered nuclear morphology without affecting the levels of lamin proteins, which are known prominent regulators of nuclear shape. In contrast, a major group of nuclear shape regulators were modifiers of repressive heterochromatin. Biochemical and molecular analysis uncovered a direct physical interaction of histone H3 with lamin A mediated via combinatorial histone modifications. Furthermore, disease-causing lamin A mutations that result in disruption of nuclear shape inhibited lamin A-histone H3 interactions. Finally, oncogenic histone H3.3 mutants defective for H3K27 methylation resulted in nuclear morphology abnormalities. Altogether, our results represent a systematic exploration of cellular factors involved in determining nuclear morphology and they identify the interaction of lamin A with histone H3 as an important contributor to nuclear morphology in human cells.

cell biology↗

bioRxiv2019

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

How intracellular organelles acquire their characteristic sizes is a fundamental cell biological question. Given the stereotypical changes in nuclear size in cancer, it is particularly important to understand the mechanisms that control nuclear size in human cells. Here we use a high-throughput imaging RNAi screen to identify and mechanistically characterize ELYS, a nucleoporin required for postmitotic nuclear pore complex (NPC) assembly, as a determinant of nuclear size in mammalian cells. We show that ELYS knockdown results in small nuclei, the accumulation of cytoplasmic lamin aggregates, reduced nuclear lamin B2 localization, lower NPC density, and decreased nuclear import. Increasing nuclear import by importin overexpression rescues nuclear size and lamin B2 import, while inhibiting importin /{beta} nuclear import decreases nuclear size. Conversely, ELYS overexpression leads to increased nuclear size, enrichment of nuclear lamin B2 staining at the nuclear periphery, and elevated NPC density and nuclear import. Consistent with these observations, knockdown or inhibition of exportin 1 increases nuclear size. In summary, we identify ELYS and NPC density as novel positive effectors of mammalian nuclear size and propose that nuclear size is controlled by nuclear import capacity.

cell biology↗

bioRxiv2019

Altering nuclear import in early Xenopus laevis embryos affects later development

More than just a container for DNA, the nucleus carries out a wide variety of critical and highly regulated cellular functions. One of these functions is nuclear import, and in this study we investigate how altering nuclear import impacts developmental progression and organismal size. During early Xenopus laevis embryogenesis, the timing of a key developmental event, the midblastula transition (MBT), is sensitive to nuclear import factor levels. How might altering nuclear import and MBT timing in the early embryo affect downstream development of the organism? We microinjected X.laevis two-cell embryos to increase levels of importin or NTF2, resulting in differential amounts of nuclear import factors in the two halves of the embryo. Compared to controls, these embryos exhibited delayed gastrulation, curved neural plates, and bent tadpoles with different sized eyes. Furthermore, embryos microinjected with NTF2 developed into smaller froglets compared to control microinjected embryos. We propose that altering nuclear import and size affects MBT timing, cell size, and cell number, subsequently disrupting later development. Thus, altering nuclear import early in development can affect function and size at the organismal level.

developmental biology↗