Genome-wide and locus-specific approaches to characterize hepatic gene regulation in cancer cachexia

Cancer-associated cachexia affects 80% of cancer patients and causes 30% of cancer deaths.Many studies have focused on the molecular mechanism of muscle wasting and adipose tissue loss in rodents or human subjects with cancer cachexia.Although the liver is a central player in body energy metabolism, its role in cachexia has rarely been studied.By investigating the gene expression profile of cachectic liver in the C26-induced cachexia mouse model, we aim to discover how this tissue contributes to energy wasting and metabolic regulation in cancer cachexia.The transcriptional profile of cachectic liver shows upregulated expression of genes involved in cholesterol biosynthesis and repressed expression of genes involved in ketogenesis and TCA cycle.Moreover, chromatin immunoprecipitation (ChIP) coupled with next generation sequencing (ChIP-seq) provides opportunities to scrutinize the genome-wide epigenetic status of the cachectic liver and identify transcriptional regulatory programs that determine this.The bioinformatic analysis of these active DNA elements could reveal the transcription factors involved in the hepatic response to cachexia.In addition to the well-known cytokine regulators implicated in cancer cachexia (such as TNFα and IL-6), the search for circulating cachectic factors has proceeded slowly.It is necessary to build a comprehensive catalogue of cachectic factors, whose contribution to energy wasting can be evaluated in different organs.We performed a time-series gene expression analysis of cachectic cells C26 and tumor tissue after xenograft transplantation.The bioinformatic analysis has identified a list of cachectic factors, which showed high similarity with Lewis Lung Carcinoma (LLC), another cachectogenic cells.To better characterize the transcriptional regulators of cholesterol biosynthesis, which is a major metabolic feature of cachectic liver, we developed a novel technology (TALE-AP) to study the DNA locus-specific transcription factor complex by repurposing TALE.We showed that TALE-AP identify SREBP1 as a transcription factor specifically binding to SQLE promoter, which is confirmed by ENCODE SummaryPrevious studies have characterized the gene expression profile of cachectic liver, but the underlying TF network mediating these transcription changes remains unknown.In this chapter, we adopted an epigenomic approach to systematically identify active DNA elements genome-wide and used bioinformatics analysis to uncover the TFs involved.To identify the active DNA regions in cachectic liver, we performed ChIP-seq against three commonly used histone modification marks (H3K4me1, H3K4me3 and H3K27ac), CTD-phosphorylated RNA polymerase II and CBP in cachectic and sham-injected liver.Pathway enrichment analysis indicated that the active genes were enriched for cytokine-cytokine receptor interaction, the insulin response pathway and JAK-STAT signaling.Motif analysis suggested that STAT3, FOX and ETS family TFs were involved in reprogramming hepatic gene expression during cachexia. 4.1

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