Fatty liver disease causes huge economic losses in the poultry industry due to its high occurrence and lethality rate. Three-dimensional (3D) chromatin architecture takes part in disease processing by regulating transcriptional reprogramming. The study is carried out to investigate the alterations of hepatic 3D genome and H3K27ac profiling in early fatty liver (FLS) and reveal their effect on hepatic transcriptional reprogramming in laying hens. Results show that FLS model is constructed with obvious phenotypes including hepatic visible lipid deposition as well as higher total triglyceride and cholesterol in serum. A/B compartment switching, topologically associating domain (TAD) and chromatin loop changes are identified by high-throughput/resolution chromosome conformation capture (HiC) technology. Targeted genes of these alternations in hepatic 3D genome organization significantly enrich pathways related to lipid metabolism and hepatic damage. H3K27ac differential peaks and differential expression genes (DEGs) identified through RNA-seq analysis are also enriched in these pathways. Notably, certain DEGs are found to correspond with changes in 3D chromatin structure and H3K27ac binding in their promoters. DNA motif analysis reveals that candidate transcription factors are implicated in regulating transcriptional reprogramming. Furthermore, disturbed folate metabolism is observed, as evidenced by lower folate levels and altered enzyme expression. Our findings establish a link between transcriptional reprogramming changes and 3D chromatin structure variations during early FLS formation, which provides candidate transcription factors and folate as targets for FLS prevention or treatment.

中文翻译：

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3D基因组结构的重组为蛋鸡早期脂肪肝病的发病机制提供了见解

脂肪肝病因其发病率高、致死率高，给养禽业造成巨大的经济损失。三维 (3D) 染色质结构通过调节转录重编程参与疾病处理。该研究旨在研究早期脂肪肝（FLS）中肝脏 3D 基因组和 H3K27ac 谱的变化，并揭示它们对蛋鸡肝脏转录重编程的影响。结果表明，构建的FLS模型具有明显的表型，包括肝脏可见的脂质沉积以及血清中总甘油三酯和胆固醇较高。通过高通量/分辨率染色体构象捕获 (HiC) 技术来识别 A/B 区室转换、拓扑关联域 (TAD) 和染色质环变化。肝脏 3D 基因组组织中这些交替的靶向基因显着丰富了与脂质代谢和肝损伤相关的途径。通过RNA-seq分析鉴定的H3K27ac差异峰和差异表达基因（DEG）也在这些通路中富集。值得注意的是，某些 DEG 被发现与其启动子中 3D 染色质结构和 H3K27ac 结合的变化相对应。DNA 基序分析揭示候选转录因子参与调节转录重编程。此外，还观察到叶酸代谢受到干扰，叶酸水平降低和酶表达改变就证明了这一点。我们的研究结果建立了早期 FLS 形成过程中转录重编程变化和 3D 染色质结构变化之间的联系，这提供了候选转录因子和叶酸作为 FLS 预防或治疗的靶点。