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Yun, H.

Publications and source records attributed to Yun, H..

24 records · Page 2Linked to original sources
bioRxiv2022

Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 co-activation

Initial clinical trials with drugs targeting epigenetic modulators - such as bromodomain and extraterminal (BET) inhibitors - demonstrate modest results in acute myeloid leukemia (AML). The main reason for this involves an increased transcriptional plasticity within AML, which allows cells to escape the therapeutic pressure. To study mechanisms of resistance, we investigated immediate epigenetic and transcriptional responses following BET inhibition, and could demonstrate that BET inhibitor-mediated release of BRD4 from chromatin is accompanied by an acute compensatory feedback loop that attenuates inhibition, or even increases expression, of specific transcriptional modules. This adaptation is most marked at key AML maintenance genes and is mediated by p300, suggesting a rational therapeutic opportunity by combining BET- and p300- inhibition. p300 activity is required during all steps of adaptation. However, the transcriptional programs that p300 regulates to induce resistance to BETi differ between AML subtypes. Remarkably, in some AMLs, p300 regulates a series of transitional transcriptional patterns that allow homeostatic adjustments during earlier stages of resistance to BET-inhibitors. In consequence, p300 remains crucial throughout all stages of resistance in sensitive AML-subtypes, although its importance declines following the development of chronic resistance to BET inhibitors in some other AMLs. Altogether, our study elucidates the mechanisms that underlie an "acute" state of resistance to BET inhibition, achieved through p300 activity, and how these mechanisms remodel to become "chronic". Importantly, however, our data also suggest that a sequential treatment with BET- and p300 inhibition may prevent resistance development, thereby improving outcomes. Key pointsO_LIA mechanistic feedback to p300 enables acute tolerance to BET inhibition. C_LIO_LIp300 regulates transcriptional networks that lead to chronic resistance to BET inhibition. C_LIO_LISequential BET-, followed by p300-inhibition, is synthetically lethal in AML, and is optimally deployed during earlier stages of resistance to BET inhibitors. C_LI

cancer biology↗
bioRxiv2022

Anaerobic degradation of acid red 73 by obligately aerobic Aspergillus tabacinus LZ-M though a self-redox mechanism

Fungi are potential biological resources for refractory organics degradation, but their anaerobic degradation of azo dyes are rarely reported. In this study, a fungus Aspergillus tabacinus LZ-M was isolated grown aerobically and degraded acid red 73 (AR73) with a decolorization rate of 90.28% in 5 days at 400 mg/L of concentration anaerobically. Metabolic pathway showed that AR73 was reduced into 2-hydroxynaphthalene and aniline then mineralized into CO2. The anaerobic self-redox process revealed electrons generated in carbon oxidation and transferred to -C-N= and -N=N, resulting in complete mineralization of AR73 in strain LZ-M. Data of transcriptome analysis showed that the benzene compounds produced from AR73 by declorizing reductase entered the catechol pathway and glycolysis process to mineralize. Enzymes involved in aromatics degradation, glycolysis processes, cytochrome C and quinone oxidoreductases were up-regulate, but the key reductase responsible to cleave AR73 to phenylhydrazine was not found. A novel enzyme Ord95 containing a glutamate S-transferase domain was identified in the unknown genes as a reductase which cleaving -C-N= in AR73 using NADH as electron donor, and three arginines key active sites. These observations reveal a new degradation mechanism of AR73 in strain LZ-M which would be potential candidate for treatment of azo dyes wastewater. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

microbiology↗
bioRxiv2020

Transcriptional analysis of immune modulatory genes in melanoma treated with PD-1 blockade

Abstract/SummaryWe aimed to characterize immunological features of melanoma patients treated with PD-1 blockade using tumor transcriptomic datasets. Response-dependent and response-independent predictors based on biological knowledge were investigated. Domain knowledge-driven regression-based analysis identified CEACAM1, CD40, B7-H3, and CD112 as key genes that determine the melanoma immune status. We devised the transcriptional deviance score (TDS) representing the individual sample-wise contribution to the immune network. The TDS not only showed good predictive power for immune checkpoint inhibitor (ICI) responses but also suggested specific gene interactions that determine ICI responses. Dynamic TDS changes following ICI treatment were related to long survival, indicating immune network modulation by ICIs occurred in responders. A predictive model incorporating B7-H3 and CEACAM1 expression, mutational status, clinical features, and the TDS showed excellent performance for ICI response. Thus, our approaches suggest a novel measure for the tumor immune temperature and provide insight into melanoma immunobiology. HighlightsO_LIWe applied outcome-independent and outcome-dependent methods to investigate melanoma immunobiology. C_LIO_LICEACAM1, CD40, B7-H3, and CD112 expression levels are key determinants of immune status. C_LIO_LIWe devised a TDS that could measure tumor immune network status at the individual level. C_LIO_LIIncorporating regression and correlation approaches greatly improves predictive power. C_LI

cancer biology↗
bioRxiv2020

Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3-D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. These analyses allow the identification of long-range cis-regulatory circuits, including a novel super-enhancer of the Hoxa locus, as well as larger and more detailed gene-regulatory networks, whose importance we demonstrate through perturbation of network members.

cancer biology↗
bioRxiv2020

Although host-related factors are important for the formation of gut microbiota, environmental factors cannot be ignored

The gut microbiome is essential to human health. However, little is known about the influence of the environment versus host-related factors (e.g. genetic background, sex, age, and body mass) in the formation of human intestinal microflora. Here, we present evidence in support of the importance of host-related factors in the establishment and maintenance of individual gut assemblages. We collected fecal samples (n = 249) from 44 Korean naval trainees and 39 healthy people living in Korea over eight weeks and sequenced the bacterial 16S rRNA genes. The following hypotheses were tested: 1) microbiome function is linked to its diversity, community structure, and genetic host-related factors, and 2) preexisting host-related factors have a more significant effect on gut microbiome formation and composition than environmental factors. For each individual, the difference between the initial gut microbiota and that after eight weeks was negligible even though the 44 naval trainees lived in the same area and received the same diet, the same amount of exercise, and the same amount of physical stress during the study. This suggests that host-related factors, rather than environmental factors, is a key determinant of individual gut microflora. Moreover, eight weeks of physical training and experiencing the same environmental conditions resulted in an increase in the species Bifidobacterium, Faecalibacterium, and Roseburia in most trainees, suggesting a healthier intestinal environment. IMPORTANCEIn order to understand the role of human gut microbiome, it is important to know how individuals gut microbiota are formed. In this study, we tested the host-related factors versus environmental factors to affect gut microbiome and found that the former have a more association. However, we also found that the controlled environment give an effect on the gut microflora as well. This study provides preliminary evidence that differences in the formation and diversity of gut microbiota within a population could be determined by host-related factors rather than environmental factors.

microbiology↗