Biology subjects

Osmanovic, D.

Publications and source records attributed to Osmanovic, D..

6 recordsLinked to original sources

bioRxiv2026

Programmable artificial RNA condensates in mammalian cells

Artificial biomolecular condensates have emerged as powerful tools to control cellular behaviors. Here we introduce a method to build artificial condensates within living mammalian cells through the design of modular RNA motifs formed by a single, short strand of RNA. These condensates emerge spontaneously, creating RNA-rich compartments that remain separated from their surrounding environment. The RNA sequences include stem-loop domains that fold as the RNA is transcribed, and then condense in the nucleus and cytoplasm through loop-loop interactions. These sequences can be optimized and diversified, enabling the generation of distinct, non-mixing condensate populations and the programmable control of their subcellular localization. The RNA motifs can also be modified to recruit small molecules, proteins, and RNA molecules in a sequence-specific manner to the RNA-rich phase. By introducing additional RNAs that link two distinct types of condensates, we can create droplets with multiple subcompartments, whose organization can be controlled by tuning the stoichiometry of different RNA sequences. These artificial condensates provide a versatile platform for studying and manipulating molecular functions inside living cells.

synthetic biology↗

bioRxiv2025

Internal phase separation in synthetic DNA condensates

Biomolecular condensates regulate cellular biochemistry by organizing enzymes, substrates and metabolites, and often acquire partially de-mixed states whereby distinct internal domains play functional roles. Despite their physiological relevance, questions remain about the principles underpinning the emergence of multi-phase condensates. Here, we present a model system of synthetic DNA nanostructures able to form monophasic or biphasic condensates. Key condensate features, including the degree of interphase mixing and the relative size and spatial arrangement of domains, can be controlled by altering nanostructure stoichiometries. The modular nature of the system facilitates an intuitive understanding of phase behavior, and enables mapping of the experimental phenomenology onto a predictive Flory-Huggins model. The experimental and theoretical framework we introduce will help address open questions on multiphase condensation in biology and aid the design of functional biomolecular condensates in vitro, in synthetic cells, and in living cells.

biophysics↗

bioRxiv2024

Population model of epigenetic inheritance of acquired adaptation to changing environments

Accumulated evidence of transgenerational inheritance of epigenetic and symbiotic changes begs the question of under which conditions inheritance of acquired changes can confer long-term advantage to the population. To address this question, we introduce a population epigenetics model of individuals undergoing stochastic and/or induced changes that are transmitted to the offspring. Potentially adaptive and maladaptive responses are represented, respectively, by environmentally driven changes that reduce and increase the individuals rate of death (i.e. reduction and increase of selective pressure). Analytic solution in a simplified case of exposure to two types of dynamic environments shows that inheritance of changes that transiently alleviate the selective pressure confers long-term advantage even when the transmitted state is maladaptive to the offspring. The benefits of inheriting environmentally driven changes that reduce the death rate within a lifetime include escape from extinction under a wide range of conditions. These advantages are even more pronounced in populations with imperfect inheritance and/or age-dependent decline in fertility. These findings show that inheritance of non-genetic changes can have tremendous benefits for the population on timescales that are much longer than the lifetime of an individual.

evolutionary biology↗

bioRxiv2022

Design principles of 3D epigenetic memory systems

The epigenetic state of a cell is associated with patterns of chemical modifications of histones ("marks") across the genome, with different marks typical of active (euchromatic) and inactive (heterochromatic) genomic regions. These mark patterns can be stable over many cell generations--a form of epigenetic memory--despite their constant erosion due to replication and other processes. Enzymes that place histone marks are often stimulated by the same marks, as if "spreading" marks between neighboring histones. But this positive feedback may not be sufficient for stable memory, raising the question of what is. In this work, we show how 3D genome organization--in particular, the compartmental segregation of euchromatin and heterochromatin-- could serve to stabilize an epigenetic memory, as long as (1) there is a large density difference between the compartments, (2) the modifying enzymes can spread marks in 3D, and (3) the enzymes are limited in abundance relative to their histone substrates. We introduce a biophysical model stylizing chromatin and its dynamics through the cell cycle, in which enzymes spread self-attracting marks on a polymer. We find that marks localize sharply and stably to the denser compartment, but over several cell generations, the model generically exhibits uncontrolled spread or global loss of marks. Strikingly, imposing limitation of the modifying enzymes--a plausible but oft-neglected element--totally changes this picture, yielding an epigenetic memory system, stable for hundreds of cell generations. Our model predicts a rich phenomenology to compare to experiments, and reveals basic design principles of putative epigenetic memory systems relying on compartmentalized 3D genome structure for their function.

biophysics↗

bioRxiv2022

The growth rate of DNA condensate droplets increases with the size of participating subunits

Liquid-liquid phase separation (LLPS) is a common phenomenon underlying the formation of dynamic membraneless organelles in biological cells, which are emerging as major players in controlling cellular functions and health. The bottom-up synthesis of biomolecular liquid systems with simple constituents, like nucleic acids and peptides, is useful to understand LLPS in nature as well as to develop programmable means to build new amorphous materials with properties matching or surpassing those observed in natural condensates. In particular, understanding which parameters determine condensate growth kinetics is essential for the synthesis of condensates with the capacity for active, dynamic behaviors. Here we use DNA nanotechnology to study artificial liquid condensates through programmable star-shaped subunits, focusing on the effects of changing subunit size. First, we show that LLPS is achieved in a six-fold range of subunit size. Second, we demonstrate that the rate of growth of condensate droplets scales with subunit size. Our investigation is supported by a general model that describes how coarsening and coalescence are expected to scale with subunit size under ideal assumptions. Beyond suggesting a route toward achieving control of LLPS kinetics via design of subunit size in synthetic liquids, our work suggests that particle size may be a key parameter in biological condensation processes.

bioengineering↗

bioRxiv2016

Darwinian Selection Induces Lamarckian Adaptation in a Holobiont Model

BackgroundThe relatively fast selection of symbiotic bacteria within hosts and the potential transmission of these bacteria across generations of hosts raise the question of whether interactions between host and bacteria support emergent adaptive capabilities beyond those of germ-free hosts.\n\nResultsTo investigate possibilities for emergent adaptations that may distinguish composite host-microbiome systems from germ-free hosts, we introduce a population genetics model of a host-microbiome system with vertical transmission of bacteria. The host and its bacteria are jointly exposed to a toxic agent, creating a toxic stress that can be alleviated by selection of resistant individuals and by secretion of a detoxification agent (\"detox\"). We show that toxic exposure in one generation of hosts leads to selection of resistant bacteria, which in turn, increases the toxic tolerance of the hosts offspring. Prolonged exposure to toxin over many host generations promotes additional form of emergent adaptation due to selection of hosts based on detox capabilities of their bacterial community as a whole (as opposed to properties of individual bacteria).\n\nConclusionsThese findings show that interactions between pure Darwinian selections of host and its bacteria can give rise to emergent adaptive capabilities, including Lamarckian-like adaptation of the host-microbiome system.

evolutionary biology↗