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Cited by 46Liver physiology and pathologyEstrogen and related hormone effectsSingle-cell and spatial transcriptomics

Interplay Between GH-regulated, Sex-biased Liver Transcriptome and Hepatic Zonation Revealed by Single-Nucleus RNA Sequencing

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Goldfarb, Christine N, Karri, Kritika, Pyatkov, Maxim, Waxman, David J·2022·Endocrinology
DOI 10.1210/endocr/bqac059PMC PMC9154260

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Abstract

The zonation of liver metabolic processes is well-characterized; however, little is known about the cell type-specificity and zonation of sexually dimorphic gene expression or its growth hormone (GH)-dependent transcriptional regulators. We address these issues using single-nucleus RNA-sequencing of 32 000 nuclei representing 9 major liver cell types. Nuclei were extracted from livers from adult male and female mice; from males infused with GH continuously, mimicking the female plasma GH pattern; and from mice exposed to TCPOBOP, a xenobiotic agonist ligand of the nuclear receptor CAR that perturbs sex-biased gene expression. Analysis of these rich transcriptomic datasets revealed the following: 1) expression of sex-biased genes and their GH-dependent transcriptional regulators is primarily restricted to hepatocytes and is not a feature of liver nonparenchymal cells; 2) many sex-biased transcripts show sex-dependent zonation within the liver lobule; 3) gene expression is substantially feminized both in periportal and pericentral hepatocytes when male mice are infused with GH continuously; 4) sequencing nuclei increases the sensitivity for detecting thousands of nuclear-enriched long-noncoding RNAs (lncRNAs) and enables determination of their liver cell type-specificity, sex-bias and hepatocyte zonation profiles; 5) the periportal to pericentral hepatocyte cell ratio is significantly higher in male than female liver; and 6) TCPOBOP exposure disrupts both sex-specific gene expression and hepatocyte zonation within the liver lobule. These findings highlight the complex interconnections between hepatic sexual dimorphism and zonation at the single-cell level and reveal how endogenous hormones and foreign chemical exposure can alter these interactions across the liver lobule with large effects both on protein-coding genes and lncRNAs.

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Cited by

Sorted by citations

Authors
Goldfarb, C. N., Karri, K., Pyatkov, M., & Waxman, D. J.
Affiliations
Boston University (US)
Corresponding author
Waxman, David J
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2022-05-04
Volume
163
Issue
7
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/endocr/bqac059
PMC
PMC9154260
OpenAlex
W4229038697
Cited by
46
References
11
Citations by year
2026: 12 · 2025: 11 · 2024: 6 · 2023: 13 · 2022: 4
FWCI
5.07
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Endocrinology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (DK121998, ES024421)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
growth hormone, sex-biased gene expression, hepatic zonation, liver lobule, hepatocyte heterogeneity, single-nucleus RNA sequencing, long non-coding RNA, TCPOBOP, hepatocyte zonation, sex differences, liver cell types
MeSH terms
Animals, Female, Liver, Male, Growth Hormone, Transcription Factors, Sequence Analysis, RNA, Hepatocytes, Mice, Transcriptome, RNA, Long Noncoding

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