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Epigenomic analysis of micro-dissected human liver reveals principles of zonated morphogenic and metabolic control

ABSTRACT: Epigenomic analysis of micro-dissected human liver reveals principles of zonated morphogenic and metabolic control

PROVIDER: PRJNA414905 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6188610.fastq.gz	Fastqsanger.gz
	SRR6188620.fastq.gz	Fastqsanger.gz
	SRR6188630.fastq.gz	Fastqsanger.gz
	SRR6188640.fastq.gz	Fastqsanger.gz
	SRR6188650.fastq.gz	Fastqsanger.gz

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Epigenomic analysis of micro-dissected human liver reveals principles of zonated morphogenic and metabolic control

Project description:To investigate the underlying molecular principles of metabolic and morphogenic zonation of the human liver lobule, we generated an integrated epigenetic map across three zones (pericentral, intermediate and periportal) by methylation and transcriptomic analysis of hepatocytes captured by laser micro-dissection. We observe a deep link between epigenetic zonation of human liver and a zonated expression of metabolic and morphogenic pathways: Key transcriptionally zonated enzymes in xenobiotic and glutamine metabolism show a strong anticorrelated methylation gradient indicating that zonal expression of these genes is partly controlled by epigenetic programs. Zonated DNA-methylation at binding sites of uniformly expressed transcription factors such as HNF4A and RXRα points to an epigenetic layer in regulatory networks and a zonated activity of their nuclear ligands and drugs such as fibrates and bile acids. The same holds for genes of the wnt morphogen pathway whose expression show a zonated methylation at binding sites of TCF4L2. A strong pericentral expression of LGR5 and AXIN2 and a corresponding expression gradient of the liver progenitor marker TBX3, indicates a predominant pericentral source of hepatocyte regeneration under steady-state conditions in humans. Conversely, the periportal expression of NOTCH and EPCAM at the border to the biliary tree as source of regeneration under injury conditions. Overall our data provide a deep understanding of molecular control of the zonal organisation in the human liver.

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Project description:A deeper epigenomic understanding of spatial organization of cells in human tissues is an important challenge. Here we report the first combined positional analysis of transcriptomes and methylomes across three micro-dissected zones (pericentral, intermediate and periportal) of human liver. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. While donors with non-alcoholic fatty liver disease show consistent gene expression differences corresponding to the severity of the disease across all zones, the relative zonated gene expression and DNA methylation patterns remain unchanged. Overall our data provide a wealth of new positional insights into zonal networks controlled by epigenetic and transcriptional gradients in human liver.

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Single-cell RNA-seq of sorted and micro-dissected mouse bone marrow cells

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