Multi-omics profiling of cholangiocytes reveals sex-specific chromatin state dynamics during hepatic cystogenesis in polycystic liver disease.

BACKGROUND & AIMS: Cholangiocytes transit from quiescence to hyperproliferation during cystogenesis in polycystic liver disease (PLD), the severity of which displays prominent sex differences. Epigenetic regulation plays important roles in cell state transition. We aimed to investigate the sex-specific epigenetic basis of hepatic cystogenesis and to develop therapeutic strategies targeting epigenetic modifications for PLD treatment. METHODS: Normal and cystic primary cholangiocytes were isolated from wild-type and PLD mice of both sexes. Chromatin states were characterized by analyzing chromatin accessibility (ATAC sequencing) and multiple histone modifications (chromatin immunoprecipitation sequencing). Differential gene expression was determined by transcriptomic analysis (RNA sequencing). Pharmacologic inhibition of epigenetic modifying enzymes was undertaken in PLD model mice. RESULTS: Through genome-wide profiling of chromatin dynamics, we revealed a profound increase of global chromatin accessibility during cystogenesis in both male and female PLD cholangiocytes. We identified a switch from H3K9me3 to H3K9ac on cis-regulatory DNA elements of cyst-associated genes and showed that inhibition of H3K9ac acetyltransferase or H3K9me3 demethylase slowed cyst growth in male, but not female, PLD mice. In contrast, we found that H3K27ac was specifically increased in female PLD mice and that genes associated with H3K27ac-gained regions were enriched for cyst-related pathways. In an integrated epigenomic and transcriptomic analysis, we identified an estrogen receptor alpha-centered transcription factor network associated with the H3K27ac-regulated cystogenic gene expression program in female PLD mice. CONCLUSIONS: Our findings highlight the multi-layered sex-specific epigenetic dynamics underlying cholangiocyte state transition and reveal a potential epigenetic therapeutic strategy for male PLD patients. IMPACT AND IMPLICATIONS: In the present study, we elucidate a sex-specific epigenetic mechanism underlying the cholangiocyte state transition during hepatic cystogenesis and identify epigenetic drugs that effectively slow cyst growth in male PLD mice. These findings underscore the importance of sex difference in the pathogenesis of PLD and may guide researchers and physicians to develop sex-specific personalized approaches for PLD treatment.

Enhanced performance and mechanisms of sulfamethoxazole removal in vertical subsurface flow constructed wetland by filling manganese ore as the substrate.

Sulfamethoxazole (SMX), a typical sulfonamide antibiotic, is ubiquitous in secondary effluent and may pose undesirable effects on the aquatic ecosystem and human health. Constructed wetland (CW) is more and more applied in advanced sewage treatment, and the substrate plays an important role in removing pollutants. Manganese (Mn) ore has been widely concerned as a new type of substrate to remove pollutants in CW due to its high adsorption and redox properties. However, the removal mechanism of antibiotics by Mn ore CW is still unclear. In this study, Mn ore was selected as the substrate of a vertical flow constructed wetland (VFCW) while gravel substrate was selected as a control group, and the removal efficiencies of SMX in two VFCWs were investigated and compared. Experimental devices were layered as different regions, including anaerobic (0-32 cm), anoxic (32-64 cm) and aerobic (64-80 cm) zones, to examine the removal characteristics of SMX in different regions. And the removal mechanism of SMX was also explored by examining the adsorption and oxidation of Mn ore and the microbial degradation performance. The results showed that the final removal efficiency of SMX in CW filled with Mn ore substrate (M-CW) (48.4%) increased by 39.6%, compared with CW filled with gravel substrate (G-CW) (8.8%). According to the calculation of mass balance, the total loss of SMX caused by the oxidation of Mn ore and biodegradation accounted for 33.0% of the total SMX input in M-CW, the SMX loss caused by the biodegradation in G-CW accounted for 13.0%, and the substrate adsorption in M-CW and G-CW occupied 15.0% and 7.0% of the total SMX input, respectively. Mn(II) was formed during the oxidation of SMX by Mn(III, IV) and dissimilated Mn(III, IV) reduction by microorganisms in anaerobic environment (0-32 cm). Whereafter, the produced Mn(II) entered into the aerobic zone (64-80 cm) with the water flow and was re-oxidized into biogenic Mn oxides (BioMnOx) which had high adsorption and oxidation performance for SMX. Therefore, Mn ore could enhance SMX removal efficiency in anaerobic and aerobic zones by Mn redox process.

Fe0-loaded superfine powdered activated carbon prepared by ball milling for synergistic adsorption and persulfate activation to remove aqueous carbamazepine.

The massive use of personal medicines makes them widely enter the aquatic environments and cause pollution, drawing a great deal of attention over the last few years. In this study, a novel nano Fe0-loaded superfine powdered activated carbon (Fe0@SPAC) was prepared via a simple ball milling method. Fe0@SPAC showed a rapid and effective removal for aqueous carbamazepine (CBZ) via the process of synergistic adsorption and persulfate (PDS) activation. The removal efficiency of CBZ (30 mg L-1) could be up to 96% by Fe0@SPAC (0.05 g L-1) with the presence of PDS (2 mM), and the maximum pseudo-first-order rate constant was 0.12 min-1. The performance of Fe0@SPAC was superior to other reported iron-bearing activator materials, and its dosage was much lower. Fe0@SPAC was also effective to remove other typical drug pollutants and had excellent reusability in five cycles. The loaded Fe0 could activate PDS to generate OH and SO4-, which played the major role for CBZ removal. It is interesting that carbon base of Fe0@SPAC could also activate PDS via surface defects, making the minor contribution to CBZ degradation. Besides, Fe0@SPAC showed rapid and high adsorption for CBZ due to the superfine particle diameter, partially contributing to CBZ removal. Finally, the possible break sites of CBZ and its degradation pathway were proposed based on DFT theoretical calculation and product identification. Fe0@SPAC would be a promising material for the removal of drug pollutants, and this study may help understand the mechanisms of synergistic adsorption and persulfate activation by carbon composite material.

Enhancement effects of dissolved organic matter leached from sewage sludge on microbial reduction and immobilization of Cr(VI) by Geobacter sulfurreducens.

Sewage sludge has a high concentration of dissolved organic matter (DOM) which contains compounds that can serve as electron donors or shuttles for metal reduction by dissimilatory metal reducing bacteria (DMRB). In this study, Cr(VI) removal by G. sulfurreducens, a common DMRB present in anaerobic soils, was examined in the presence or absence of sludge DOM. Two different types of sludge DOM were tested; composted sludge DOM (C-DOM) and anaerobically digested sludge DOM (A-DOM). Both sludge DOMs enhanced Cr(VI) reduction by G. sulfurreducens, but C-DOM was more effective likely because it had higher concentrations of humic substances that served as electron shuttles. Transcriptomic studies indicated that G. sulfurreducens utilizes several different mechanisms to tolerate chromium including extracellular Cr(VI) reduction and immobilization by outer membrane c-type cytochromes and electrically conductive pili, intracellular Cr(VI) reduction by triheme cytochromes and NAD(P)H FMN reductase proteins, and chromium efflux by several P-type ATPase and RND transporter proteins. Microscopy experiments also showed that Cr(III) crystals formed on the surface of the cells, indicating that extracellular Cr(VI) reduction and adsorption was involved in the chromium removal process. These results help provide insight into the potential use of sewage sludge as an additive to enhance the bioremediation of chromium contaminated soils.