Nonmodular oscillator and switch based on RNA decay drive regeneration of multimodal gene expression

Periodic gene expression dynamics are key to cell and organism physiology. Studies of oscillatory expression have focused on networks with intuitive regulatory negative feedback loops, leaving unknown whether other common biochemical reactions can produce oscillations. Oscillation and noise have been proposed to support the capacity of mammalian progenitor cells to restore heterogenous, multimodal expression from extreme subpopulations, but underlying networks and specific roles of noise remained elusive. We use mass-action-based models to show that regulated RNA degradation involving as few as two RNA species, applicable to nearly half of human protein-coding genes, can generate sustained oscillations without imposed feedback. Diverging oscillation periods synergize with noise to robustly restore bimodal expression in cell populations. The global bifurcation organizing this divergence relies on an oscillator and bistable switch which cannot be decomposed into two structural modules. Our work reveals surprisingly rich dynamics of post-transcriptional reactions and a potentially widespread mechanism useful for development and regeneration.

A chromosomal inversion may facilitate adaptation despite periodic gene flow in a freshwater fish

Genomic architecture, such as chromosomal inversions, may play an important role in facilitating adaptation despite opportunities for gene flow. One system where chromosomal inversions may be important for eco-evolutionary dynamics are in freshwater fish, which often live in heterogenous environments characterized by varying levels of connectivity and varying opportunities for gene flow. In the present study, reduced representation sequencing was used to study possible adaptation in n=345 walleye (Sander vitreus) from three North American waterbodies: Cedar Bluff Reservoir (Kansas, USA), Lake Manitoba (Manitoba, Canada), and Lake Winnipeg (Manitoba, Canada). Haplotype and outlier-based tests revealed a putative chromosomal inversion that contained three expressed genes and was nearly fixed for alternate genotypes in each Canadian lake. These patterns exist despite several opportunities for gene flow between these proximate Canadian lakes, suggesting that the inversion may be important for facilitating adaptative divergence between the two lakes despite gene flow. Our study illuminates the importance of genomic architecture for facilitating local adaptation in freshwater fish and provides additional evidence that inversions may facilitate local adaptation in many organisms that inhabit connected but heterogenous environments.

Stress induced Differential Expression of THAP9 & THAP9-AS1 in the S-phase of cell cycle

Transposable elements function as one of the major effectors in response to biological or environmental stress. Under normal conditions, host organisms deploy epigenetic and post-transcriptional machinery (histone modifications, chromatin remodelers, long non-coding RNAs (lncRNAs)) at the TE sites to contain their mobility. But many a times, the chromatin architecture undergoes TE induced changes under the effect of stress that in turn might lead to unprecedented gene expression. LncRNAs are emerging as a crucial tool in the regulation of TEs. TEs possess remarkable abilities to respond in the face of stress, ranging from undetected mutations to changing the regulatory landscape of the host. Although the relationship between stress response and TE activation/deactivation is well acknowledged but our understanding of the mechanism of regulation remains poor.This study focuses on the gene expression of THAP9, a domesticated transposon and lncRNA THAP9-AS1 (THAP9-anti sense1), which form a sense and anti-sense gene pair with a promoter overlap of approximately 350bp. The two genes exhibit different patterns of gene expression under different types of stresses in the S-phase of the cell cycle. THAP9-AS1 is always upregulated under stress whereas THAP9 exhibits both downregulation and upregulation in different stresses. Both THAP9 and THAP9-AS1 exhibit a periodic gene expression throughout the S-phase which is a characteristic of cell cycle regulated genes.

Cell wall remodeling and vesicle trafficking mediate the root clock in Arabidopsis

In Arabidopsis thaliana, lateral roots initiate in a process preceded by periodic gene expression known as the root clock. We identified the vesicle-trafficking regulator GNOM and its suppressor, ADENOSINE PHOSPHATE RIBOSYLATION FACTOR GTPase ACTIVATION PROTEIN DOMAIN3, as root clock regulators. GNOM is required for the proper distribution of pectin, a mediator of intercellular adhesion, whereas the pectin esterification state is essential for a functional root clock. In sites of lateral root primordia emergence, both esterified and de-esterified pectin variants are differentially distributed. Using a reverse-genetics approach, we show that genes controlling pectin esterification regulate the root clock and lateral root initiation. These results indicate that the balance between esterified and de-esterified pectin states is essential for proper root clock function and the subsequent initiation of lateral root primordia.

Cell wall remodeling and vesicle trafficking mediate the root clock in Arabidopsis

In Arabidopsis, lateral roots initiate along the primary root in a process preceded by periodic gene expression, a phenomenon known as the root clock. Many genes involved in lateral root initiation have been identified. However, very little is known about the structural changes underlying the initiation process nor about how root clock function is regulated. In genetic screens, we identified the vesicle trafficking regulators, GNOM and its suppressor, AGD3, as critical to root clock function. We show that GNOM is required for the proper distribution of pectin, a mediator of intercellular adhesion, and that pectin esterification state is essential for a functional root clock. We found that in sites of lateral root primordia emergence, both esterified and de-esterified pectin are differentially distributed. Using a reverse genetic approach, we identified significant enrichment of GO terms associated with pectin modifying enzymes in the oscillation zone were the root clock is established. In agreement with a recent study on the function of pectin in pavement cell morphogenesis, our results indicate that the balance between esterified and de-esterified pectin is essential for proper root clock function and the subsequent initiation of lateral root primordia.

Bacterial variability in the mammalian gut captured by a single-cell synthetic oscillator

Synthetic gene oscillators have the potential to control timed functions and periodic gene expression in engineered cells. Such oscillators have been refined in bacteria in vitro, however, these systems have lacked the robustness and precision necessary for applications in complex in vivo environments, such as the mammalian gut. Here, we demonstrate the implementation of a synthetic oscillator capable of keeping robust time in the mouse gut over periods of days. The oscillations provide a marker of bacterial growth at a single-cell level enabling quantification of bacterial dynamics in response to inflammation and underlying variations in the gut microbiota. Our work directly detects increased bacterial growth heterogeneity during disease and differences between spatial niches in the gut, demonstrating the deployment of a precise engineered genetic oscillator in real-life settings.

On the relative ease of speciation with periodic gene flow

Common models of speciation with gene flow consider constant migration or admixture on secondary contact, but earth’s recent climatic history suggests many populations have experienced cycles of isolation and contact over the last million years. How does this process impact the rate of speciation, and how much can we learn about its dynamics by analyzing the genomes of modern populations? Here we develop a simple model of speciation through Bateson-Dobzhansky-Muller incompatibilities in the face of periodic gene flow and validate our model with forward time simulations. We then use empirical atmospheric CO2 concentration data from the Vostok Ice Cores to simulate cycles of isolation and secondary contact in a tropical montane landscape, and ask whether they can be distinguished from a standard isolation-with-migration model by summary statistics or joint site frequency spectrum-based demographic inference. We find speciation occurs much faster under periodic than constant gene flow with equivalent effective migration rates (Nm). These processes can be distinguished through combinations of summary statistics or demographic inference from the site frequency spectrum, but parameter estimates appear to have little resolution beyond the most recent cycle of isolation and migration. Our results suggest speciation with periodic gene flow is a common force in generating species diversity through Pleistocene climate cycles, and highlight the limits of current inference techniques for demographic models mimicking the complexity of earth’s recent climatic history.

Rhythmic chromatin interactions with lamin B1 reflect stochasticity in variable lamina-associated domains during the circadian cycle

Many mammalian genes exhibit circadian expression patterns concordant with periodic binding of transcription factors, chromatin modifications and chromosomal interactions. Here, we report periodic interactions of chromatin with nuclear lamins, suggesting rhythmic associations with the nuclear lamina. Entrainment of the circadian clock is accompanied in mouse liver by a gain of lamin B1-chromatin interactions, followed by oscillations in these interactions at hundreds of lamina-associated domains (LADs). A subset of these oscillations exhibit distinct 12, 18, 24 or 30-h periodicity in our dataset, and affect one or both LAD borders or entire stand-alone LADs. However, most LADs are conserved during the circadian cycle, and periodic LADs are seldom occurrences rather than dominant features of variable LADs. Periodic LADs display oscillation asynchrony between 5’ and 3’ LAD borders, and are uncoupled from periodic gene expression within or in vicinity of these LADs. Accordingly, periodic genes, including central clock-control genes, are often located megabases away from LADs, suggesting residence in a transcriptionally permissive environment throughout the circadian cycle. Autonomous oscillatory associations of the genome with nuclear lamins provide new evidence for rhythmic spatial chromatin configurations. Nevertheless, our data suggest that periodic LADs reflect stochasticity in lamin-chromatin interactions underlying chromatin dynamics in the liver during the circadian cycle. They also argue that periodic gene expression is by and large not regulated by rhythmic chromatin associations with the nuclear lamina.

INO80 Chromatin Remodelling Coordinates Metabolic Homeostasis with Cell Division

ABSTRACTAdaptive survival requires the coordination of nutrient availability with expenditure of cellular resources. For example, in nutrient-limited environments, 50% of all S. cerevisiae genes synchronize and exhibit periodic bursts of expression in coordination with respiration and cell division in the Yeast Metabolic Cycle (YMC). Despite the importance of metabolic and proliferative synchrony, the majority of YMC regulators are currently unknown. Here we demonstrate that the INO80 chromatin-remodelling complex is required to coordinate respiration and cell division with periodic gene expression. Specifically, INO80 mutants have severe defects in oxygen consumption and promiscuous cell division that is no longer coupled with metabolic status. In mutant cells, chromatin accessibility of periodic genes, including TORC-responsive genes, is relatively static, concomitant with severely attenuated gene expression. Collectively, these results reveal that the INO80 complex mediates metabolic signaling to chromatin in order to restrict proliferation to metabolically optimal states.