A Multi-Omics Approach to Liver Diseases : Integration of Single Nuclei Transcriptomics with Proteomics and HiCap Bulk Data in Human Liver

• The liver is the largest solid organ and a primary metabolic hub. In recent years, intact cell nuclei were used to perform single-nuclei RNA-seq (snRNA-seq) for tissues difficult to dissociate and for flash-frozen archived tissue samples to discover unknown and rare cell subpopulations. In this study, we performed snRNA-seq of a liver sample to identify subpopulations of cells based on nuclear transcriptomics. In 4282 single nuclei, we detected, on average, 1377 active genes and we identified seven major cell types. We integrated data from 94,286 distal interactions (p < 0.05) for 7682 promoters from a targeted chromosome conformation capture technique (HiCap) and mass spectrometry proteomics for the same liver sample. We observed a reasonable correlation between proteomics and in silico bulk snRNA-seq (r = 0.47) using tissue-independent gene-specific protein abundancy estimation factors. We specifically looked at genes of medical importance. The DPYD gene is involved in the pharmacogenetics of fluoropyrimidine toxicity and some of its variants are analyzed for clinical purposes. We identified a new putative polymorphic regulatory element, which may contribute to variation in toxicity. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and we investigated all known risk genes. We identified a complex regulatory landscape for the SLC2A2 gene with 16 candidate enhancers. Three of them harbor somatic motif breaking and other mutations in HCC in the Pan Cancer Analysis of Whole Genomes dataset and are candidates to contribute to malignancy. Our results highlight the potential of a multi-omics approach in the study of human diseases.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

human liver

multi-omics data integration

proteomics

snRNA-seq

ADAMTS protein

ADAMTS2 protein

albumin

biological marker

cadherin

cadherin 11

CD163 antigen

CD74 antigen

collagen type 3

collagen type 6

cystic fibrosis transmembrane conductance regulator

dihydropyrimidine dehydrogenase

epithelial cell adhesion molecule

fibroblast growth factor 1

fluorouracil

glucose transporter 1

glucose transporter 2

interleukin 18

messenger RNA

nostrin

proteome

small nuclear RNA

somatomedin binding protein 3

transcription factor Sox4

transcription factor Sox9

transcriptome

unclassified drug

vasculotropin receptor 1

apoa2 gene

Article

c3 gene

controlled study

dcn gene

enhancer region

eps2 gene

f5 gene

f8 gene

fgb gene

fgl1 gene

g6pc gene

gene

gene identification

human

human cell

human chromosome

human tissue

intron

lamb1 gene

liver cell carcinoma

liver parenchyma

lrp2 gene

marker gene

mass spectrometry

multiomics

mup3 gene

myo1f gene

oit3 gene

pck1 gene

plekhg1 gene

plg gene

priority journal

promoter region

ptprb gene

RNA conformation

RNA sequencing

single nucleotide polymorphism

spp1 gene

transcriptomics

Publikations- och innehållstyp

ref (ämneskategori)

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