ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation
Open accessAbstract
AXIN2 and LGR5 mark intestinal stem cells (ISCs) that require WNT/β-Catenin signaling for constant homeostatic proliferation. In contrast, AXIN2/LGR5+ pericentral hepatocytes show low proliferation rates despite a WNT/β-Catenin activity gradient required for metabolic liver zonation. The mechanisms restricting proliferation in AXIN2+ hepatocytes and metabolic gene expression in AXIN2+ ISCs remained elusive. We now show that restricted chromatin accessibility in ISCs prevents the expression of β-Catenin-regulated metabolic enzymes, whereas fine-tuning of WNT/β-Catenin activity by ZNRF3 and RNF43 restricts proliferation in chromatin-permissive AXIN2+ hepatocytes, while preserving metabolic function. ZNRF3 deletion promotes hepatocyte proliferation, which in turn becomes limited by RNF43 upregulation. Concomitant deletion of RNF43 in ZNRF3 mutant mice results in metabolic reprogramming of periportal hepatocytes and induces clonal expansion in a subset of hepatocytes, ultimately promoting liver tumors. Together, ZNRF3 and RNF43 cooperate to safeguard liver homeostasis by spatially and temporally restricting WNT/β-Catenin activity, balancing metabolic function and hepatocyte proliferation.
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eGRN inference shows that expression of periportal and pericentral genes is directly regulated at the chromatin level, contrary to recently published studies that focused on the accessibility of their promoters.
“Together, eGRN inference shows that expression of periportal and pericentral genes is directly regulated at the chromatin level, contrary to recently published studies that focused on the accessibility of their promoters34 (Extended Data Fig. 5a,b).”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [34]
Metabolic zonation is dynamic and requires active activation and repression of metabolic gene expression.
“Zonal reprogramming observed by spatial transcriptomics22 and molecular cartography25 combined with perturbation of WNT/β-catenin signalling further indicate that metabolic zonation is dynamic and requires active activation and repression of metabolic gene expression.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
WNT/β-catenin signalling controlled by the RSPO-LGR4/5-ZNRF3/RNF43 module is a major determinant of hepatocyte identity and metabolic function in the liver.
“WNT/β-catenin signalling controlled by the RSPO-LGR4/5-ZNRF3/RNF43 module is a major determinant of hepatocyte identity and metabolic function in the liver.22,[42], [43], [44], [45], [46], [47], [48]”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
Activation of WNT/β-catenin signalling reprogrammed periportal into pericentral hepatocytes, while pathway blockage induced widespread periportal metabolic enzyme expression.
“While activation of WNT/β-catenin signalling reprogrammed periportal into pericentral hepatocytes, pathway blockage induced widespread periportal metabolic enzyme expression.22,42,44,45,51”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
ZNRF3/RNF43 deletion reprogrammed periportal hepatocytes into pericentral hepatocytes.
“ZNRF3/RNF43 deletion reprogrammed periportal hepatocytes into pericentral hepatocytes.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
Since the same pathways that induce and maintain metabolic function also control hepatocyte proliferation, restricting unnecessary proliferation while maintaining the metabolic identity of hepatocytes in the different zones is an important balancing act for the liver.
“Since the same pathways that induce and maintain metabolic function also control hepatocyte proliferation, restricting unnecessary proliferation while maintaining the metabolic identity of hepatocytes in the different zones is an important balancing act for the liver.22,76”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
ZNRF3 and RNF43 cooperate to restrict WNT/β-catenin signalling during homeostasis to prevent uncontrolled proliferation and tumour formation, while enabling metabolic zonation.
“ZNRF3 and RNF43 cooperate to restrict WNT/β-catenin signalling during homeostasis to prevent uncontrolled proliferation and tumour formation, while enabling metabolic zonation.22,92”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
Proliferative hepatocytes are mostly located in zone 2.
“Spatial transcriptomics profiling identified proliferative hepatocytes mostly in zone 2,22 consistent with the lineage-tracing studies described above.75,86,88”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
Proliferative hepatocytes show significantly reduced expression of metabolic genes.
“Interestingly, these proliferative hepatocytes showed significantly reduced expression of metabolic genes.22”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
Some hepatocytes with ZNRF3/RNF43 deletion increased metabolic gene expression, whereas others proliferated.
“A curious and still unresolved finding was that some hepatocytes with ZNRF3/RNF43 deletion increased metabolic gene expression, whereas others proliferated.22”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
Hepatocytes in all lobular zones have accessible chromatin in genes regulating proliferation and periportal and pericentral metabolism.
“However, hepatocytes in all lobular zones have accessible chromatin in the genes regulating proliferation, as well as periportal and pericentral metabolism.22”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
Redundant regulatory mechanisms, such as ZNRF3 and RNF43, balance WNT/β-catenin activity and prevent tumour formation.
“Redundant regulatory mechanisms, such as the two ubiquitin ligases ZNRF3 and RNF43,22,92 therefore balance WNT/β-catenin activity and prevent tumour formation.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [22]
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- Authors
- Sun, T., Annunziato, S., Bergling, S., Sheng, C., Orsini, V., Forcella, P., Pikiolek, M., Kancherla, V., Holwerda, S., Imanci, D., Wu, F., Meylan, L. C., Puehringer, L. F., Waldt, A., Oertli, M., Schuierer, S., Terracciano, L. M., Reinker, S., Ruffner, H., Bouwmeester, T., Sailer, A. W., George, E., Roma, G., de Weck, A., Piscuoglio, S., Lohmann, F., Naumann, U., Liberali, P., Cong, F., & Tchorz, J. S.
- Affiliations
- Novartis (Switzerland) (CH)
- University of Basel (CH)
- Humanitas University (IT)
- Corresponding author
- Sun, Tianliang
- Tchorz, Jan S.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 28
- Issue
- 10
- Pages
- 1822-1837.e10
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W3168111723
- Cited by
- 84
- References
- 13
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 17 · 2023: 20 · 2022: 15 · 2021: 2
- FWCI
- 4.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- The Novartis Repository (Novartis) (acceptedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- ZNRF3, RNF43, Wnt/β-catenin signaling, liver zonation, hepatocyte proliferation, Axin2, Lgr5, intestinal stem cells, chromatin accessibility, metabolic reprogramming, liver homeostasis, liver tumors, clonal expansion, periportal hepatocytes
- MeSH terms
- Animals, Liver, Stem Cells, Hepatocytes, Ubiquitin-Protein Ligases, Cell Proliferation, beta Catenin, Mice, Wnt Signaling Pathway
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