Biology subjects

Niess, H.

Publications and source records attributed to Niess, H..

5 recordsLinked to original sources

bioRxiv2026

Transient suppression of the ECM1 gatekeeper is essential for HGF/c-MET-driven liver regeneration

Hepatocyte growth factor (HGF) is a multifunctional cytokine stored in the extracellular matrix as an inactive precursor and is essential for tissue repair. How HGF activity is dynamically regulated during regeneration remains unclear. Here, we identify extracellular matrix protein 1 (ECM1) as a physiological inhibitor of active HGF during liver regeneration. Following 70% partial hepatectomy, active HGF rapidly increases in parallel with a sharp decline in ECM1, and preventing this downregulation delays liver mass recovery. Mechanistically, ECM1 directly binds the active HGF -subunit through a mechanism dependent on residue R392, thereby suppressing c-MET-ERK-MYC signaling and hepatocyte proliferation. Loss of ECM1 permits activation of this pathway, whereas MYC overexpression rescues ECM1-mediated growth inhibition. In patients, proliferative hepatocytes localize to ECM1-negative regions. Supported by transcriptomic analyses and computational modeling, these findings identify ECM1 as an extracellular gatekeeper whose transient downregulation enables HGF-driven tissue repair. HighlightsO_LIECM1 is temporally downregulated during liver regeneration, while forced ECM1 expression delays liver mass recovery after 70% PHx by suppressing hepatocyte proliferation. C_LIO_LIRapid and transient ECM1 downregulation permits HGF-c-Met-ERK-MYC signaling to drive hepatocyte cell-cycle entry and expansion. C_LIO_LIECM1 directly binds the active HGF -subunit with residue R392 playing a critical role, revealing a novel extracellular mechanism for growth factor inhibition. C_LIO_LILoss of ECM1 marks proliferative hepatocytes in human liver repair, identifying ECM1 as a tunable regulator of regenerative capacity. C_LI

cell biology↗

bioRxiv2026

Mapping the MIF-2 Chemokine Interactome Reveals MIF-2-CCL20 Complex Formation in Liver Fibrosis

D-dopachrome tautomerase (D-DT/MIF-2) is an inflammatory cytokine, atypical chemokine (ACK) and member of the macrophage migration-inhibitory factor (MIF) family. While interactions among classical chemokines (CKs) are established, ACK-CK interactions remain underexplored. Here, we screened for MIF-2 binding-partners using a protein array encompassing all CKs and selected ACKs, and validated candidate interactors by surface-plasmon resonance. CCL20/MIP-3 was prioritized based on RNA-sequencing suggesting induction during liver fibrosis. MIF-2/CCL20 complex formation was verified by microscale thermophoresis and interaction interfaces mapped using peptide array and in-silico modeling. The deduced binding-site near the MIF-2 tautomerase pocket was consistent with inhibition of its tautomerase activity by CCL20. We found both proteins abundantly expressed in human liver tissue, with a positive correlation. Pull-down confirmed complex formation and proximity ligation assay demonstrated MIF-2/CCL20 complexes in liver in situ, with higher levels in fibrotic tissue. Functionally, MIF-2/CCL20 complexes suppressed MIF-2-driven CD4 T-cell chemotaxis and fibroblast IL-6 secretion, indicating modulation of immune and stromal responses. This study extends the ACK interactome to MIF-2 and suggests ACK/CK complexes modulate chemokine activities in liver fibrosis.

immunology↗

bioRxiv2025

Regulation of essential hepatocyte functions and identity by super-enhancers in health and disease

Physiologically, hepatocytes perform an estimated 500 essential liver functions to ensure systemic homeostasis. The mechanisms how hepatocytes maintain these numerous crucial functions in response to physiological and pathophysiological challenges are largely unknown. In this study, we found that vital liver function genes (e.g., HNF4A, ALB, coagulation factors, and SLC2A2) in hepatocytes possess super-enhancers. Interfering with the super-enhancers by dCas9-sgRNA remarkably decreases the expression of these genes. Quiescent liver progenitor cells (LPCs) do not have active super-enhancers in vital liver function genes. In acute liver failure (ALF) caused by massive hepatic necrosis, activated LPCs perform liver function and differentiate into hepatocytes to rescue patients lives. We show that activated LPCs gradually form super-enhancers in liver function genes (e.g., HNF4A, ALB, and coagulation factors) during proliferation and differentiation. These super-enhancers are regulated by FOXA2 through the recruitment of HNF4 a, p300 and Mediators in most liver function genes, such as ALB and coagulation factors. However, super-enhancers in some genes (e.g., SLC2A2) are FOXA2-indenpendent. Hepatic FOXA2 expression is closely associated with the clinical outcome of ALF. In a cohort of ALF patients, robust FOXA2 is observed only in the surviving patients. Collectively, super-enhancers represent a critical epigenetic regulatory mechanism that enables rapidly enhanced transcription of liver function genes in response to pathophysiological challenges. In urgent clinical syndrome such as ALF, LPCs rescue liver function by rapid formation of super-enhancers in vital genes.

molecular biology↗

bioRxiv2023

FOXA2 is essential for maintaining the urea cycle in acute liver failure

Hepatic encephalopathy is a lethal complication of acute liver failure (ALF), and is caused by hyperammonemia. Ammonia clearance by the liver requires an intact and complete urea cycle comprising six enzymes, including the rate-limiting enzyme carbamoyl phosphate synthetase I (CPS1). To date, the detailed regulation of CPS1 transcription in order to maintain urea cycle in physiological condition and ALF remains largely unknown. This study scrutinizes the role of pioneer factor forkhead box A 2 (FOXA2) in the regulation of CPS1 transcription, urea cycle performance and hyperammonemia. Physiologically, CPS1 transcription requires FOXA2 to maintain chromatin accessibility on its enhancers, which is essential for CCAAT enhancer-binding protein-alpha (C/EBP) binding to activate gene transcription. In ALF, hepatic C/EBP expression is inhibited by inflammatory mediators such as TGF-{beta} and TNF-. In this setting, retinoic acid receptor synergizes with FOXA2 to maintain CPS1 transcriptions. Once ALF patients suffer from massive hepatic necrosis, liver progenitor cells initiate a transcription network comprising FOXA2 and C/EBP to perform the urea cycle and prevent hyperammonemia. In ALF, hepatic encephalopathy occurs in patients lacking hepatic FOXA2 expression. In mice with acetaminophen-induced ALF, injection of Foxa2-AAV8 maintains urea cycle and prevents hyperammonemia. Taken together, FOXA2 is essential for maintaining the urea cycle. Pharmaceutical induction of hepatic FOXA2 expression might represent a novel approach to treat hepatic encephalopathy in ALF. One Sentence SummaryPioneer factor FOXA2 synergizes with C/EBP or RAR to maintain urea cycle in acute liver failure

molecular biology↗

bioRxiv2023

Insulin determines the effects of TGF-beta on HNF4alpha transcription and epithelial-to-mesenchymal transition in hepatocytes

To date, epithelial-to-mesenchymal transition (EMT) has been observed in cultured hepatocytes, but not in vivo. TGF-{beta} is supposed to initiate EMT in hepatocytes by inhibiting HNF4 through the SMAD2/3 complex. We report that TGF-{beta} does not directly inhibit HNF4, but contributes to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CBP/p300 to the HNF4 promoter. The recruitment of CBP/p300 is indispensable for C/EBPa binding, another essential requirement for constitutive HNF4 expression in hepatocytes. In contrast to the observed induction of HNF4, SMAD2/3 inhibits C/EBP transcription. Therefore, long-term TGF-{beta} incubation results in C/EBP depletion, which abrogates HNF4 expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBP promoter is abolished by insulin. Thus, maintaining a high insulin concentration in culture medium ensures constitutive HNF4 and thereby prevents TGF-{beta}-induced hepatocyte EMT. Furthermore, insulin inhibits TGF-{beta}-induced SMAD2/3 binding to the promoters of core EMT transcription factors e.g., SNAI1. SNAI1 transcription requires both SMAD2/3 and FOXO1 in nuclei. Insulin inhibits SNAI1 transcription through impeding SMAD2/3 binding to its promoter and inducing FOXO1 phosphorylation. Hence, insulin is the key factor that prevents TGF-{beta}-induced EMT in hepatocytes.

cell biology↗