A genomics approach to study the non-parenchymal cell population of the liver

Trine Vestergaard Dam

doi:10.21996/gmex-mf38

A genomics approach to study the non-parenchymal cell population of the liver

Trine Vestergaard Dam

Publikation: Afhandling › Ph.d.-afhandling

142 Downloads (Pure)

Abstract

Forekomsten af fedme er stigende på verdensplan. Sygdommen påvirker stort set alle væv ved atinducere systemiske metaboliske ubalancer. En stor del af den overskydende energi i fedme ophobesi leveren, hvilket medfører leversteatose, som videre kan inducere inflammation og fibrose i vævet.Ultimativt kan dette føre til fedtleverbetændelse (NASH). Indsigt i sygdomsmekanismer er essentieltfor udvikling af nye sygdomsterapier. Lipotoksisk stress inducerer celledød og frigivelse af proinflammatoriske cytokiner i leveren, hvilket medfører infiltrering af immuncellepopulationer. Leverensspecialiserede celletypepopulationer påvirkes betydeligt af dette ændrede vævsmiljø. For eksempel,dedifferentierer de sinusoide endotelceller, hvilket medvirker til aktivering af fibrogene stellatceller.I de senere år har vi opnået uvurderlig viden om celletype-heterogenitet i NASH igennem enkeltcelleRNA-sekventering. Dog er der stadigvæk mange ukendte faktorer i det ikke-kodende genom, somudgør en forbindelse mellem vævssignaler og en celles genekspressionsrespons. I denne afhandlingpræsenterer jeg resultater fra en diæt-induceret NASH musemodel, hvori det cis-regulatoriske genomkortlægges ved brug af enkeltkerne ATAC/RNA-sekventering. Vi detekterede de forventede celletyper i en NASH-kontekst og kunne bekræfte det cis-regulatoriske genoms celletypedefinerende karakter, idet

Originalsprog	Engelsk
Bevilgende institution	Syddansk Universitet
Vejledere/rådgivere	Grøntved, Lars, Hovedvejleder Madsen, Jesper Grud Skat, Bivejleder Krag, Aleksander, Bivejleder
Eksterne samarbejdspartnere	Joshua Waterfall
Dato for forsvar	22. feb. 2023
Udgiver	Syddansk Universitet. Det Naturvidenskabelige Fakultet
DOI	https://doi.org/10.21996/gmex-mf38
Status	Udgivet - 14. apr. 2023

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10.21996/gmex-mf38

Open Access VersionForlagets udgivne version, 13,8 MB

1 Tidsskriftartikel

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD
Dam, T. V., Toft, N. I. & Grøntved, L., 1. mar. 2022, I: Cells. 11, 5, 870.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Citationsformater

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abstract = "Obesity prevalence is increasing worldwide. It impacts virtually all tissues by inducing systemic metabolic imbalances. The liver is a major site for energy disposal in obesity leading to hepatosteatosisthat may further boost hepatic inflammation and fibrogenesis leading to non-alcoholic steatohepatitis(NASH). Insights into disease mechanisms are required for the development of novel therapies. Lipotoxic stress induce hepatocellular death and the release of proinflammatory cytokines that triggerimmune cell infiltration and activation of resident cell types. Moreover, dedifferentiation of liversinusoidal endothelial cells (LSECs) drives stellate cell activation in turn exaggerating fibrogenesis.In recent years we have obtained invaluable insight into cell type heterogeneity in NASH due to theexpansion of single cell transcriptomics. However, insight into the cis-regulatory genome serving asthe link between niche signals and gene expression outcome is lacking. We applied a diet-inducedmouse model of NASH to map the cis-regulatory regions (CRR) involved in NASH using singlenucleus ATAC sequencing and single nucleus RNA-sequencing combined with a genetic approachto deplete hepatocyte nuclei. We detected the expected repertoire of non-parenchymal cell types in aNASH context and confirmed the highly cell type-defining nature of the cis-regulatory genome as",

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N2 - Obesity prevalence is increasing worldwide. It impacts virtually all tissues by inducing systemic metabolic imbalances. The liver is a major site for energy disposal in obesity leading to hepatosteatosisthat may further boost hepatic inflammation and fibrogenesis leading to non-alcoholic steatohepatitis(NASH). Insights into disease mechanisms are required for the development of novel therapies. Lipotoxic stress induce hepatocellular death and the release of proinflammatory cytokines that triggerimmune cell infiltration and activation of resident cell types. Moreover, dedifferentiation of liversinusoidal endothelial cells (LSECs) drives stellate cell activation in turn exaggerating fibrogenesis.In recent years we have obtained invaluable insight into cell type heterogeneity in NASH due to theexpansion of single cell transcriptomics. However, insight into the cis-regulatory genome serving asthe link between niche signals and gene expression outcome is lacking. We applied a diet-inducedmouse model of NASH to map the cis-regulatory regions (CRR) involved in NASH using singlenucleus ATAC sequencing and single nucleus RNA-sequencing combined with a genetic approachto deplete hepatocyte nuclei. We detected the expected repertoire of non-parenchymal cell types in aNASH context and confirmed the highly cell type-defining nature of the cis-regulatory genome as

AB - Obesity prevalence is increasing worldwide. It impacts virtually all tissues by inducing systemic metabolic imbalances. The liver is a major site for energy disposal in obesity leading to hepatosteatosisthat may further boost hepatic inflammation and fibrogenesis leading to non-alcoholic steatohepatitis(NASH). Insights into disease mechanisms are required for the development of novel therapies. Lipotoxic stress induce hepatocellular death and the release of proinflammatory cytokines that triggerimmune cell infiltration and activation of resident cell types. Moreover, dedifferentiation of liversinusoidal endothelial cells (LSECs) drives stellate cell activation in turn exaggerating fibrogenesis.In recent years we have obtained invaluable insight into cell type heterogeneity in NASH due to theexpansion of single cell transcriptomics. However, insight into the cis-regulatory genome serving asthe link between niche signals and gene expression outcome is lacking. We applied a diet-inducedmouse model of NASH to map the cis-regulatory regions (CRR) involved in NASH using singlenucleus ATAC sequencing and single nucleus RNA-sequencing combined with a genetic approachto deplete hepatocyte nuclei. We detected the expected repertoire of non-parenchymal cell types in aNASH context and confirmed the highly cell type-defining nature of the cis-regulatory genome as

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DO - 10.21996/gmex-mf38

M3 - Ph.D. thesis

PB - Syddansk Universitet. Det Naturvidenskabelige Fakultet

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A genomics approach to study the non-parenchymal cell population of the liver

Abstract

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Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

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