A novel comparative pattern analysis approach identifies chronic alcohol mediated dysregulation of transcriptomic dynamics during liver regeneration

Kuttippurathu, Lakshmi; Juskeviciute, Egle; Dippold, Rachael P.; Hoek, Jan B.; Vadigepalli, Rajanikanth

doi:10.1186/s12864-016-2492-x

Cited by 17 publications

(23 citation statements)

References 99 publications

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“…Our data also show that the ALD Liver-Chip picked up the impact of ethanol treatment on genes involved in the metabolism of alanine, aspartate, and glutamate. In line with previous data shown the link between FLD and DNA damage in hepatocytes 18 , our analysis revealed upregulation of POLE and POLD2 61 , both involved in DNA replication and repair, as well as of RAD51 and FANCB, which are expressed at DNA damage sites and implicated in homologous recombination 62,63 (Fig. 3e).…”

Section: Ethanol-induced Steatosis In the Liver-chipsupporting

confidence: 92%

Modeling alcoholic liver disease in a human Liver-Chip

Nawroth

et al. 2020

Preprint

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Fatty liver disease (FLD), is a major public health burden that affects up to 30% of people in Western countries and leads to progressive liver injury, comorbidities, and increased mortality. Key risk factors for developing FLD are obesity and alcohol consumption, both of which are growing in prevalence worldwide. There is an urgent need for human-relevant preclinical models to improve our understanding of FLD progression to steatohepatitis and for the development of sensitive noninvasive diagnostics and therapies. Alcohol-induced liver disease (ALD) represents an ideal case for modeling FDL as ethanol exposure is a comparatively simpler trigger for experimental induction of the pathology, as opposed to the complexity of modeling the diet- and life-style induced FLD. Further, despite their different root causes several common characteristics in disease progression and deterioration of liver function in the two disease entities, highlighting the potential of an ALD microphysiological model for broad application in translational research. Here, we leverage our recently reported human Liver-Chip for toxicity applications, to expand the capabilities of the platform for broad application in translational research. We report the first in vitro modeling of ALD that uses human relevant blood alcohol concentrations (BAC) and affords multimodal profiling of clinically relevant endpoints. Our ALD Liver-Chip recapitulates established FLD markers in response to ethanol in a concentration-dependent manner, including lipid accumulation and oxidative stress. Importantly, we show that the ALD Liver-Chip supports the study of secondary insults, as patients with advanced ALD often show high blood endotoxin levels due to alcohol-associated increased intestinal permeability and barrier dysfunction. Moreover, owing to new developments in the design, the ALD Liver-Chip enables the measurement of structural changes of the bile canaliculi (BC) network as a novel in vitro quantitative readout of alcoholic liver toxicity. In summary, we report the development of a human ALD Liver-Chip as a new platform for modeling the progression of alcohol-induced liver injury with direct translation to clinical research.

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Section: Ethanol-induced Steatosis In the Liver-chipsupporting

confidence: 92%

Modeling alcoholic liver disease in a human Liver-Chip

Nawroth

et al. 2020

Preprint

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“…In order to unmask the potential effects of RA and DEAB treatments on transcriptomic changes during early development, we analyzed the clutch-averaged data using an unbiased dynamic pattern analysis approach to categorize the gene expression profiles along all possible discretized patterns (Kuttippurathu et al, 2016). Each pattern is based on the direction of up- or down-regulation above a 2-fold threshold (three possibilities: up-regulation, down-regulation, or no change) at each of the three recovery time points relative to the stage the treatment was terminated (early gastrula; t=0), yielding 3*3*3 = 27 possible discretized patterns.…”

Section: Resultsmentioning

confidence: 99%

“…To compare the RA and DEAB groups for their effect on gene expression relative to the unperturbed temporal pattern observed in the control samples, we adapted a recently developed unbiased approach named COMPACT for analyzing time-series differential transcriptomic profiles across multiple experimental conditions (Kuttippurathu et al, 2016). In this scheme, we started with the statistically significant genes within each treatment group (two-way ANOVA; q<0.05), and constructed discrete patterns based on differential gene expression between RA and control groups (81 possible patterns, with up-, down- and no-regulation at t=0, 1.5, 3 and 4.5 h).…”

Section: Resultsmentioning

confidence: 99%

“…Although this classification is qualitative and there might be differences in intensity, it suggests a limited repertoire of RA regulatory responses. To further understand the regulation of RA targets we performed a comparative analysis of the patterns observed during increased and decreased RA levels using our unbiased approach, COMPACT (Kuttippurathu et al, 2016). This analysis revealed that most genes (75.40%) responding to RA manipulation and recovery exhibited a response to either increased or decreased RA levels.…”

Section: Discussionmentioning

confidence: 99%

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Retinoic acid fluctuation activates an uneven, direction-dependent network-wide robustness response in early embryogenesis

Parihar

Bendelac-Kapon

Gur

et al. 2020

Preprint

Self Cite

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Retinoic acid (RA) is a central developmental signal whose perturbation results in teratogenic outcomes. We performed transient physiological RA signaling disturbances during embryogenesis followed by kinetic RNAseq and high-throughput qPCR analysis of the recovery. Unbiased comparative pattern analysis identified the RA network as a key differentially regulated module aimed at achieving RA signaling robustness. We analyzed this module using a principal curve-based approach determining clutch-wise variability, and organized the results into a robustness efficiency matrix comparing the shifts in RA feedback regulation and hox gene expression. We found that feedback autoregulation was sensitive to the direction of the RA perturbation: RA knock-down exhibited an upper response limit, whereas RA addition did not activate a feedback response below a threshold. These results suggest an asymmetric capacity for robust feedback control of RA signal during early development based on genetic polymorphisms, likely a significant contributor to the manifestation of developmental defects.

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“…Chronic alcohol consumption causes oxidative mitochondria DNA (mtDNA) damage in hepatocytes and inhibits liver regeneration after partial hepatectomy . However, our previous publication showed that a reduced‐size (50%) liver from rats fed alcohol regenerated well when transplanted to a normal host.…”

mentioning

confidence: 99%

Fibrosis in small syngeneic rat liver grafts because of damaged bone marrow stem cells from chronic alcohol consumption

Hisada¹,

Zhang²,

Ota³

et al. 2017

Liver Transpl

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A patient with liver failure due to chronic and acute alcohol abuse under consideration for an urgent liver transplant shortly after stopping alcohol may have residual abnormalities that threaten transplant success, particularly for a small graft. To address this, we studied a model in which reduced-size (50%) Lewis rat livers are transplanted into green fluorescence protein transgenic Lewis recipients after they are fed alcohol or a control diet for 5 weeks. Here we show that normal small Lewis grafts transplanted to alcohol-fed Lewis hosts developed fibrosis, whereas no fibrosis was observed in control-fed recipients. Host-derived CD133 + 8-hydroxy-2'-deoxyguanosine (8-OHdG) cells were significantly increased in livers recovered from both alcohol-fed and control recipients, but only alcohol-fed recipients demonstrated co-staining (a marker of oxidative DNA damage). α smooth muscle actin (α-SMA) staining, a marker for myofibroblasts, also co-localized with CD133 + cells only in the livers of alcohol-fed recipients. Immunostaining and polymerase chain reaction analysis confirmed that chronic alcohol consumption decreased the proportion of bone marrow stem cells (BMSCs) expressing CD133, c-Kit, and chemokine (C-X-C motif) receptor 4 markers and caused oxidative mitochondria DNA (mtDNA) damage. Culture of CD133 + cells from normal rats with medium containing 3% ethanol for 48 hours resulted in elevated mitochondrial 8-OHdG and mtDNA deletion, and ethanol exposure diminished CD133 expression but dramatically increased α-SMA expression. In conclusion, oxidative mtDNA damage and deletions occur in BMSCs of chronic alcohol-fed recipients, and these damaged cells mobilize to the small liver grafts and become myofibroblasts where they play a key role in the subsequent development of fibrosis. Liver Transplantation 23 1564-1576 2017 AASLD.

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A novel comparative pattern analysis approach identifies chronic alcohol mediated dysregulation of transcriptomic dynamics during liver regeneration

Cited by 17 publications

References 99 publications

Modeling alcoholic liver disease in a human Liver-Chip

Modeling alcoholic liver disease in a human Liver-Chip

Retinoic acid fluctuation activates an uneven, direction-dependent network-wide robustness response in early embryogenesis

Fibrosis in small syngeneic rat liver grafts because of damaged bone marrow stem cells from chronic alcohol consumption

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