Biology subjects

Park, H. J.

Publications and source records attributed to Park, H. J..

4 recordsLinked to original sources

bioRxiv2018

Stochastic population dynamics driven by mutant interactors

Spontaneous random mutations are an important source of variation in populations. Many evolutionary models consider mutants with a fixed fitness chosen from a certain fitness distribution without considering any interactions among the residents and mutants. Here, we go beyond this and consider \"mutant interactors\", which lead to new interactions between the residents and invading mutants that can affect the carrying capacity and the extinction risk of populations. We model microscopic interactions between individuals by using a dynamical payoff matrix and analyze the stochastic dynamics of such populations. New interactions drawn from invading mutants can drive the population away from the previous equilibrium, and lead to changes in the population size -- the population size is an evolving property rather than a fixed number or externally controlled variable. We present analytical results for the average population size over time and quantify the extinction risk of the population by the mean time to extinction.

evolutionary biology↗

bioRxiv2018

Targeting glutamine metabolism and redox state for leukemia therapy

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional genotoxic chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. Here, we show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating acute lymphoblastic leukemia cells in vitro and in vivo. Thus, targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.\n\nKey PointsO_LIGlutaminase inhibition commonly impairs glutathione metabolism and induces mitochondrial oxidative stress in acute myeloid leukemia cells\nC_LIO_LIA glutaminase inhibitor synergizes with pro-oxidant drugs in inducing apoptosis and eliminating leukemia cells in vitro and in vivo\nC_LI

cancer biology↗

bioRxiv2018

Ecological feedback on diffusion dynamics

Spatial patterns are ubiquitous across different scales of organization. Animal coat pattern, spatial organization of insect colonies, and vegetation in arid areas are prominent examples from such diverse ecologies. Typically, pattern formation has been described by reaction-diffusion equations, which considers individuals dispersing between sub-populations of a global pool. This framework applied to public goods game nicely showed the endurance of populations via diffusion and generation of spatial patterns. However, how the spatial characteristics, such as diffusion, are related to the eco-evolutionary process as well as the nature of the feedback from evolution to ecology and vice versa, has been so far neglected. We present a thorough analysis of the ecologically driven evolutionary dynamics in a spatially extended version of ecological public goods games. We show how these evolutionary dynamics feedback into shaping the ecology thus together determining the fate of the system.

evolutionary biology↗

bioRxiv2017

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures

Thrombopoietin (TPO) is a critical cytokine regulating hematopoietic stem cell maintenance and differentiation into the megakaryocytic lineage. However, the transcriptional and chromatin dynamics elicited by TPO signaling are poorly understood. Here, we study the immediate early transcriptional and cis-regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relation between cis-regulatory activity and chromatin architecture. We show that TPO profoundly alters the transcriptome of HSPCs, with key hematopoietic regulators being transcriptionally repressed within 30 minutes of TPO. By examining cis-regulatory dynamics and chromatin architectures, we demonstrate that these changes are accompanied by rapid and extensive epigenome remodeling of cis-regulatory landscapes that is spatially coordinated within topologically associating domains (TADs). Moreover, TPO-responsive enhancers are spatially clustered and engage in preferential homotypic intra- and inter-TAD interactions that are largely refractory to TPO signaling. By further examining the link between cis-regulatory dynamics and chromatin looping, we show that rapid modulation of cis-regulatory activity is largely independent of chromatin looping dynamics. Finally, we show that, although activated and repressed cis-regulatory elements share remarkably similar DNA sequence compositions, transcription factor binding patterns accurately predict rapid cis-regulatory responses to TPO.

genomics↗