Dysregulated H3K27 Acetylation Is Implicated in Fatty Liver Hemorrhagic Syndrome in Chickens.

Yaling Zhu,Jiming Ruan,Jianzhen Huang,Qing Wei,Tao Jiang,Zhimin Zhou,Chao Yin,Qingjie Zeng,Haoshu Fang,Yujie Wang,Fang Li

doi:10.3389/fgene.2020.574167

Abstract

Epigenetic regulation of gene expression has been reported in the pathogenesis of metabolic disorders such as diabetes and liver steatosis in humans. However, the molecular mechanisms of fatty liver hemorrhagic syndrome (FLHS) in chickens have been rarely studied. H3K27ac chromatin immunoprecipitation coupled with high-throughput sequencing and high-throughput RNA sequencing was performed to compare genome-wide H3K27ac profiles and transcriptomes of liver tissue between healthy and FLHS chickens. In total, 1,321 differential H3K27ac regions and 443 differentially expressed genes were identified (| log2Fold change| ≥ 1 and P-value ≤ 0.05) between the two groups. Binding motifs for transcription factors involved in immune processes and metabolic homeostasis were enriched among those differential H3K27ac regions. Differential H3K27ac peaks were associated with multiple known FLHS risk genes, involved in lipid and energy metabolism (PCK1, APOA1, ANGPTL4, and FABP1) and the immune system (FGF7, PDGFRA, and KIT). Previous studies and our current results suggested that the high-energy, low-protein (HELP) diet might have an impact on histone modification and chromatin structure, leading to the dysregulation of candidate genes and the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which causes excessive accumulation of fat in the liver tissue and induces the development of FLHS. These findings highlight that epigenetic modifications contribute to the regulation of gene expression and play a central regulatory role in FLHS. The PPAR signaling pathway and other genes implicated in FLHS are of great importance for the development of novel and specific therapies for FLHS-susceptible commercial laying hens.

Highlights

Fatty liver hemorrhagic syndrome (FLHS) is a lipid metabolism disorder, which is characterized by a dramatic drop in egg production and increased mortality of commercial laying hens, in turn causing considerable economic losses (Hansen and Walzem, 1993; Trott et al, 2014; Rozenboim et al, 2016)
Fatty liver hemorrhagic syndrome-affected chickens had large, friable, and soft livers in contrast to healthy hens (Figure 1A), and the color varied from yellow to orange (Figure 1B), which is consistent with previous reports (Spurlock and Savage, 1993; FIGURE 4 | Differential H3K27ac peaks associated with fatty liver hemorrhagic syndrome (FLHS) in the liver. (A) Top 10 significant differential H3K27ac peaks between healthy and FLHS chickens. (B) Representative validation of differential peaks exhibiting distinct activity of the H3K27ac signal across healthy and FLHS chickens
As metabolic disorders such as obesity and liver steatosis often stem from the dysregulation of lipid homeostasis and immune pathways (Steinberg, 2007; Gurzov et al, 2016), our study revealed that differentially acetylated peaks were involved in the regulation of a number of genes enriched in lipid metabolism, glucose homeostasis, and immune biological processes, including PCK1, APOA1, ANGPTL4, FABP1, NTRK2, FGF7, PDGFRA, and KIT

Summary

Introduction

Fatty liver hemorrhagic syndrome (FLHS) is a lipid metabolism disorder, which is characterized by a dramatic drop in egg production and increased mortality of commercial laying hens, in turn causing considerable economic losses (Hansen and Walzem, 1993; Trott et al, 2014; Rozenboim et al, 2016). Despite of the progress made in understanding the risk factors that contribute to FLHS, the epigenetic mechanism via which nutrition drives FLHS susceptibility remain elusive, and adaptive changes in epigenetic and transcriptional regulation play an important role in the phenotypic adaptation of cells to the environment (Corradin and Scacheri, 2014; Lee et al, 2014; Nammo et al, 2018). Many reports support the notion that epigenomic dysregulation may influence transcriptional output and signaling pathways, providing a mechanistic basis for investigating its involvement in various common diseases, such as non-alcoholic fatty liver (NAFLD), diabetes, Alzheimer’s diseases, and others (Ling and Groop, 2009; Lee et al, 2014; Marzi et al, 2018; Nammo et al, 2018). No systematic study has examined the regulatory modifications of FLHS in chicken

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