Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control

Brosch, Mario; Kattler, Kathrin; Herrmann, Alexander; Schönfels, Witigo von; Nordström, Karl; Seehofer, Daniel; Damm, Georg; Becker, Thomas; Zeißig, Sebastian; Nehring, Sophie; Reichel, F; Moser, V. Alexandra; Thangapandi, RV; Stickel, Felix; Baretton, G; Röcken, Christoph; Muders, Michael H.; Matz‐Soja, Madlen; Krawczak, Michael; Gasparoni, Gilles; Hartmann, Hella; Dahl, Andreas; Schafmayer, Clemens; Walter, Joern; Hampe, Jochen

doi:10.1055/s-0038-1677063

Cited by 20 publications

(48 citation statements)

References 33 publications

(46 reference statements)

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“…The mRNA levels of Hnf4a were not zonated, whereas the protein content was higher in the periportal gates. This periportal protein bias is in line with previously reported involvement of Hnf4a in periportal repression of Wnt regulated pericentral genes [17][18][19] and induction of periportally expressed targets 20 . Thus, our analysis indicates that the majority of proteins and mRNAs are similarly zonated, and highlight genes with potential post-transcriptional regulation.…”

Section: Zonation Patterns Of the Hepatocyte Proteomesupporting

confidence: 91%

Spatial sorting enables comprehensive characterization of liver zonation

Ben‐Moshe

Shapira

Moor

et al. 2019

Preprint

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Switzerland* Correspondence: shalev.itzkovitz@weizmann.ac.il † These authors contributed equally.The mammalian liver is composed of repeating hexagonal units termed lobules. Spatiallyresolved single-cell transcriptomics revealed that about half of hepatocyte genes are differentially expressed across the lobule. Technical limitations impede reconstructing similar global spatial maps of other hepatocyte features. Here, we used zonated surface markers to sort hepatocytes from defined lobule zones with high spatial resolution. We applied transcriptomics, microRNA array measurements and Mass-spectrometry proteomics to reconstruct spatial atlases of multiple zonated hepatocyte features. We found that protein zonation largely overlapped mRNA zonation. We identified zonation of key microRNAs such as miR-122, and inverse zonation of microRNAs and their hepatocyte gene targets, implying potential regulation through zonated mRNA degradation. These targets included the pericentral Wnt receptors Fzd7 and Fzd8 and the periportal Wnt inhibitors Tcf7l1 and Ctnnbip1. Our approach facilitates reconstruction of spatial atlases of multiple cellular features in the liver and in other structured tissues.

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Section: Zonation Patterns Of the Hepatocyte Proteomesupporting

confidence: 91%

Spatial sorting enables comprehensive characterization of liver zonation

Ben‐Moshe

Shapira

Moor

et al. 2019

Preprint

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“…For example, HNF4A, a core hepatic TF that regulates the expression of several other liver TFs and is required for normal liver development and function, was only zonated at protein level, showing higher protein content in periportal hepatocytes (Ben‐Moshe et al, ; Figure ). This zonation at protein level is in line with the role of HNF4A in repressing pericentral genes in periportal regions (Colletti et al, ; Stanulović et al, ), and in activating periportal genes (Brosch et al, ). Thus far, similar studies have not been performed in human liver tissue.…”

Section: Liver Transcriptional Programssupporting

confidence: 61%

“…There is nevertheless suggestive evidence indicating that different gene regulatory processes accompany liver zonation. DNA methylation studies have shown that changes in the overall epigenomic landscape accompany differences in gene expression, namely via differential methylation of HNF4A and TCF7L2 binding sites along the porto‐central axis (Brosch et al, ). Moreover, mice lacking Dicer, a key element in the processing of miRNAs, display widespread changes in liver zonation (Sekine, Ogawa, McManus, Kanai, & Hebrok, ), indicating that miRNAs are involved in the regulation of zonated gene expression.…”

Section: Liver Cis‐regulatory Networkmentioning

confidence: 99%

Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

Cebola

2020

WIREs Mechanisms of Disease

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Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) result from complex interactions between intrinsic and extrinsic factors, including genetics and exposure to obesogenic environments. These risk factors converge in aberrant gene expression patterns in the liver, which are underlined by altered cis‐regulatory networks. In homeostasis and in disease states, liver cis‐regulatory networks are established by coordinated action of liver‐enriched transcription factors (TFs), which define enhancer landscapes, activating broad gene programs with spatiotemporal resolution. Recent advances in DNA sequencing have dramatically expanded our ability to map active transcripts, enhancers and TF cistromes, and to define the 3D chromatin topology that contains these elements. Deployment of these technologies has allowed investigation of the molecular processes that regulate liver development and metabolic homeostasis. Moreover, genomic studies of NAFLD patients and NAFLD models have demonstrated that the liver undergoes pervasive regulatory rewiring in NAFLD, which is reflected by aberrant gene expression profiles. We have therefore achieved an unprecedented level of detail in the understanding of liver cis‐regulatory networks, particularly in physiological conditions. Future studies should aim to map active regulatory elements with added levels of resolution, addressing how the chromatin landscapes of different cell lineages contribute to and are altered in NAFLD and NAFLD‐associated metabolic states. Such efforts would provide additional clues into the molecular factors that trigger this disease. This article is categorized under: Biological Mechanisms > Metabolism Biological Mechanisms > Regulatory Biology Laboratory Methods and Technologies > Genetic/Genomic Methods

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“…Apart from mutation or expression abnormalities, Wnt, PI3K‐Akt as well as E‐cadherin are tightly controlled by DNA methylation. Recent studies demonstrated that epigenetic activation of Wnt signaling (marked by enhanced β‐catenin and silent RNF43) is prevalently observed in multiple types of cancer . Reduced methylation of PTEN CpG islands suppresses, while hyper‐methylation of PTEN CpG islands stimulates PI3K‐Akt signaling .…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies demonstrated that epigenetic activation of Wnt signaling (marked by enhanced β-catenin and silent RNF43) is prevalently observed in multiple types of cancer. [47][48][49] Reduced methylation of PTEN CpG islands suppresses, while hyper-methylation of PTEN CpG islands stimulates PI3K-Akt signaling. 50,51 Methylation of CDH1 CpG islands also increases in malignant tissues and contributes to tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

et al. 2019

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Background As the most abundant epigenetic modification on mRNAs and long non‐coding RNAs, N6‐methyladenosine (m6A) modification extensively exists in mammalian cells. Controlled by writers (methyltransferases), readers (signal transducers), and erasers (demethylases), m6A influences mRNA structure, maturation, and stability, thus negatively regulating protein expression in a post‐translational manner. Nevertheless, current understanding of m6A's roles in tumorigenesis, especially in gastric cancer (GC) remains to be unveiled. In this study, we assessed m6A's clinicopathological relevance to GC and explored the underlying mechanisms. Methods By referring to a proteomics‐based GC cohort we previously generated and the TCGA‐GC cohort, we merged expressions of canonical m6A writers (METTL3/METTL14), readers (YTHDF1/YTHDF2/YTHDF3), and erasers (ALKBH5/FTO), respectively, as W, R, and E signatures to represent m6A modification. We stratified patients according to these signatures to decipher m6A's associations with crucial mutations, prognosis, and clinical indexes. m6A's biological functions in GC were predicted by gene set enrichment analysis (GSEA) and validated by in vitro experiments. Results We discovered that W and R were potential tumor suppressive signatures, while E was a potential oncogenic signature in GC. According to W/R/E stratifications, patients with low m6A‐indications were accompanied with higher mutations of specific genes ( CDH1 , AR , GLI3 , SETBP1 , RHOA , MUC6 , and TP53 ) and also demonstrated adverse clinical outcomes. GSEA suggested that reduced m6A was correlated with oncogenic signaling and phenotypes. Through in vitro experiments, we proved that m6A suppression (represented by METTL14 knockdown) promoted GC cell proliferation and invasiveness through activating Wnt and PI3K‐Akt signaling, while m6A elevation (represented by FTO knockdown) reversed these phenotypical and molecular changes. m6A may also be involved in interferon signaling and immune responses of GC. Conclusions Our work demonstrated that low‐m6A signatures predicted adverse clinicopathological features of GC, while the reduction of RNA m6A methylation activated oncogenic Wnt/PI3K‐Akt signaling and promoted malignant phenotypes of GC cells.

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Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control

Cited by 20 publications

References 33 publications

Spatial sorting enables comprehensive characterization of liver zonation

Spatial sorting enables comprehensive characterization of liver zonation

Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

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