Roux-en-Y gastric bypass-induced perturbative changes in microbial communities and metabolic pathways in rats.

Background: Obesity has become a global health and socioeconomic problem because of an inadequate balance between energy intake and energy expenditure. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the two most commonly used strategies for weight loss, which have been proven to benefit from gut microbiota restoration. Methods: Rats received SG, RYGB, and sham operations for 10 weeks. At the end of the experiment, the fecal microbiota was analyzed using 16s rRNA gene sequencing. In addition, the shift in the plasma metabolism of rats that underwent RYGB surgery was analyzed using untargeted metabolomics. The crosstalk between microbiome and metabolites was revealed using metabolic pathway enrichment and integrated analysis. Result: The SG surgery induced a modest shift in the gut microbiota relative to the RYGB. RYGB significantly decreased the alpha diversity and Firmicutes/Bacteroides (F/B) ratio and increased the proportion of Escherichia, Bacteroides, and Akkermansia genera compared to sham and SG operations. The predicted function of gut microbiota revealed that the RYGB surgery uniquely enhanced the capability of linoleic acid and sphingolipid metabolism. Furthermore, the circulating serine, phosphatidylcholine (PC) 20:5/22:5, riboflavin, L-carnitine, and linoleic acid were evaluated after RYGB surgery. In addition, the metabolic pathway enrichment and integrated analysis suggest that the RYGB induced Escherichia, Bacteroides, and Akkermansia might inhibit the sphingonine and phytosphingosine metabolisms from serine and promote the PC (20:5/22:5) metabolism to produce linoleic acid. Conclusion: This comprehensive analysis not only revealed the difference in the gut microbiota shifts after SG and RYGB but also discovered the perturbative changes in microbial communities and metabolic pathways after RYGB surgery, which provided clues for improving the beneficial effect of RYGB in metabolic disease intervention via regulating bacterial-metabolite crosstalk.

Inhibition of Arid1a increases stem/progenitor cell-like properties of liver cancer.

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, exhibits recurrent mutations in various types of human cancers, including liver cancer. However, the function of ARID1A in the pathogenesis of liver cancer remains controversial. Here, we demonstrate that Arid1a knockout may result in states of different cell differentiation, as indicated by single-cell RNA sequencing (scRNA-seq) analysis. Bulk RNA-seq also revealed that Arid1a deficiency upregulated these genes related to cell stemness and differentiation, but downregulated genes related to the hepatic functions. Furthermore, we confirmed that deficiency of Arid1a increased the expression of hepatic stem/progenitor cell markers, such as Cd133 and Epcam, and enhanced the self-renewal ability of cells. Mechanistic studies revealed that Arid1a loss remodeled the chromatin accessibility of some genes related to liver functions. Thus, Arid1a deficiency might contribute to cancer development by increasing the number of stem/progenitor-like cells through dysregulating the expression of these genes related to cell stemness, differentiation and liver functions.

BRD4 inhibition induces synthetic lethality in ARID2-deficient hepatocellular carcinoma by increasing DNA damage.

Hepatocellular carcinoma (HCC) has emerged as the third cause of cancer-related death owing to lacking effective systemic therapies. Genomic DNA sequencing revealed the high frequency of loss-of-function mutations in ARID2, which encodes a subunit of SWI/SNF chromatin remodeling complex, however, the therapeutic strategy for the HCC patients with ARID2 mutations is still completely unclear. In this study, we first performed a high-throughput screening approach using a compound library consisting of 2 180 FDA-approved drugs and other compounds, to elicit the potential drugs for synthetic lethality to target ARID2-deficient HCC cells. Interestingly, JQ1, a selective inhibitor of bromodomain protein BRD4, uniquely suppressed the growth of ARID2- deficient HCC cells. Next JQ1 is further confirmed to predominantly induce cell lethality upon ARID2 depletion through exacerbating DNA damage, especially double strand breaks (DSBs). Functional assays demonstrated that both BRD4 inhibition and ARID2 deficiency synergistically impede two main DNA damage repair pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ), through attenuating the transcription of BRCA1, RAD51, and 53BP1, which encode the core molecules responsible for DSB repair. Mechanistically, both ARID2 and BRD4 exert a synergistic effect for maintaining transcriptional enhancer-promoter loops of these genes within chromatin conformation. However, as both ARID2 and BRD4 are disrupted, the expression of these DNA repair-related genes in response to DNA damage are hindered, resulting in DSB accumulation and cell apoptosis. Taken together, this study discloses that BRD4 inhibition may induce synthetic lethality in ARID2-deficient HCC cells, which might provide a potential therapeutic strategy for HCC patients with ARID2 mutations.

ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives liver cancer cell metastasis.

ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including liver cancer. Previous studies have demonstrated that ARID1A deficiency can cause liver cancer metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms remain poorly understood. To address the effect of Arid1a deficiency on chromatin organization, we generated chromatin interaction matrices, and exploited the conformation changes upon Arid1a depletion in hepatocytes. Our results demonstrated that Arid1a deficiency induced A/B compartment switching, topologically associated domain (TAD) remodeling, and decrease of chromatin loops. Further mechanism studies revealed that ATPase BRG1 of SWI/SNF complex could physically interact with RAD21, a structural subunit of chromatin architectural element cohesin; whereas ARID1A deficiency significantly diminished the coupled BRG1-RAD21. Interestingly, the tumor-associated genes within the switched compartments were differentially expressed depending upon Arid1a depletion or not. As a consequence of ARID1A deficiency-induced conformational alteration, the dysregulation of some genes such as PMP22 and GSC, promoted the invasion capacity of liver cancer cells. This study provides an insight into liver cancer tumorigenesis and progression related to ARID1A mutations.