Biology subjects

Brunner, T.

Publications and source records attributed to Brunner, T..

5 recordsLinked to original sources

bioRxiv2026

SpiE is a distinct gut microbial 4-cholesten-3-one 5β-reductase that acts with SpiR to convert cholesterol to coprostanol

Gut microbes convert cholesterol into coprostanol, a poorly absorbed sterol that is largely excreted in feces and is linked to lower serum cholesterol levels. However, the enzymes responsible for this process remain poorly characterized. The second step of the pathway, cholestenone reduction into coprostanone, has long been established, yet the enzyme(s) responsible were unknown. Here, we use comparative genomics to identify SpiE, a cholestenone (4-cholesten-3-one) reductase that is part of the steroid processing (spi) pathway with SpiR. We confirm that SpiE binds to and reduces both cholestenone and progesterone into 5{beta}-reduced forms. SpiR and SpiE together convert cholesterol into coprostanol, indicating that both enzymes are sufficient for coprostanol formation. SpiE belongs to the short-chain dehydrogenase (SDR) family and represents an evolutionarily distinct lineage of SDR ene-reductases. Metagenomic analyses reveal that spiE relative abundance is strongly correlated with stool coprostanol (Spearman's {rho}=0.81, p=5.99e-65). In longitudinal patient cohorts, antibiotic treatment coincided with loss of SpiE and coprostanol production. Post antibiotics, the emergence of distinct SpiE-encoding genera rescued coprostanol production in some individuals. Our findings provide the biochemical basis of the cholesterol to coprostanol pathway and lay the groundwork for future studies linking it to host physiology.

microbiology↗

bioRxiv2026

Nuclear receptor LRH-1 regulates early T cell development in mice

T cell development in the thymus requires tightly coordinated transcriptional programs that regulate lineage commitment, proliferation and differentiation. While key transcription factors controlling these processes have been extensively characterized, the contribution of the low expressed nuclear receptor Liver Receptor Homolog 1 (LRH-1, Nr5a2) in T cell development remains unexplored. Here, we investigated the role of LRH-1 in thymocyte maturation using an inducible ex vivo deletion system and in vivo Lck-Cre- and CD4-Cre-mediated LRH-1 knockout mouse models. We demonstrate that inducible LRH-1 deletion impairs early thymocyte development, identifying LRH-1 as a critical regulator of the double negative (DN)2/DN3 to DN4 transition. Early Lck-Cre-mediated deletion of LRH-1, but not CD4-Cre-mediated deletion at the double positive stage, resulted in markedly reduced thymic size and cellularity, indicating a stage-specific requirement for LRH-1 during thymopoiesis. Lck-Cre-mediated LRH-1 deletion led to a decreased frequency of mature CD4 T cells in peripheral lymphoid organs, while the remaining mature T cells were predominantly Cre reporter-negative and therefore escaped LRH-1 deletion. CD4 T cells that escaped Cre-mediated LRH-1 deletion exhibited impaired T cell activation marker expression and cytokine secretion. In vivo, these defects resulted in attenuated T cell effector function and compromised regulatory T cell-mediated protection in a T cell transfer model of colitis, indicating impaired effector and regulatory T cell function under (patho)physiological conditions. Collectively, our findings identify LRH-1 as a critical, previously unrecognized regulator of early thymocyte development, and establish its essential role in shaping functional peripheral CD4 T cell-mediated immune responses.

immunology↗

bioRxiv2024

An oncoembryology approach uncovers SoxC-driven regulation of colon development and cancer

Reactivated embryonic programs are associated with cancer progression, yet their role and regulatory mechanisms remain poorly understood. In this study, we introduce oncoembryology, an approach that systematically compares embryonic and cancerous tissues to identify shared molecular programs and assess their functional relevance in disease. Applying this strategy to colorectal cancer, we identified SoxC transcription factors (Sox4, Sox11, Sox12) as critical regulators of both embryonic development and tumorigenesis. SoxC transcription factors regulate diverse downstream targets, including Tead2, Mdk, and Klf4, thereby regulating crucial steps of colon development. Abrogating SoxC function in murine models reduced tumor growth and prevented liver metastasis. Concordantly, a SoxC-driven oncoembryonic gene signature correlated with poor survival in colorectal cancer patients, underscoring the therapeutic potential of targeting SoxC-regulated pathways in cancer treatment.

cancer biology↗

bioRxiv2023

Liver Receptor Homolog-1 (LRH-1/NR5A2) orchestrates hepatic inflammation and TNF-induced cell death

Liver Receptor Homolog-1 (LRH-1/NR5A2) is a nuclear receptor that has been shown to promote apoptosis resistance in various tissues and disease contexts, however, its role in liver cell death remains unexplored. Deletion of LRH-1 in hepatocytes developed into a mild steatosis and inflammation already under steady-state conditions. Unexpectedly, hepatocyte-specific deletion of LRH-1 also resulted in a profound protection of mice from TNF-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes showed elevated NF-B activity, while LRH-1 overexpression inhibited NF-B activity. This inhibition was based on direct physical interaction of the ligand-binding domain of LRH-1 and the Rel homology domain of NF-B subunit RelA. Mechanistically, we found that increased transcription of anti-apoptotic NF-B target genes, together with proteasomal degradation of pro-apoptotic BIM via regeneration-driven EGF receptor signaling, prevented mitochondrial apoptosis, ultimately protecting mice from TNF-induced liver damage. Collectively, our study demonstrates that LRH-1 is a critical modulator of cell death and inflammation in the healthy and diseased liver. HighlightsO_LIHepatic LRH-1 deletion causes mild liver steatosis, fibrosis, and inflammation. C_LIO_LIFemale LRH-1-deficient mice are protected from TNF-induced liver damage. C_LIO_LILRH-1 interacts with NF-B and inhibits its activity. C_LIO_LILRH-1 deletion-provoked inflammation causes degradation of pro-apoptotic protein BIM. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/542039v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@13cd609org.highwire.dtl.DTLVardef@1080012org.highwire.dtl.DTLVardef@3cd9c4org.highwire.dtl.DTLVardef@fd0438_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

Regulation of PD1 signaling is associated with prognosis in glioblastoma multiforme

Glioblastoma is an aggressive cancer of the brain and spine. While analysis of glioblastoma omics data has somewhat improved our understanding of the disease, it has not led to direct improvement in patient survival. Cancer survival is often characterized by differences in expression of particular genes, but the mechanisms that drive these differences are generally unknown. We therefore set out to model the regulatory mechanisms that associate with glioblastoma survival. We inferred individual patient gene regulatory networks using data from two different expression platforms from The Cancer Genome Atlas (n=522 and 431). We performed a comparative network analysis between patients with long- and short-term survival, correcting for patient age, sex, and neoadjuvant treatment status. We identified seven pathways associated with survival, all of which were involved in immune system signaling. Differential regulation of PD1 signaling was validated in an independent dataset from the German Glioma Network (n=70). We found that transcriptional repression of genes in this pathway--for which treatment options are available--was lost in short-term survivors and that this was independent of mutation burden and only weakly associated with T-cell infiltrate. These results provide a new way to stratify glioblastoma patients that uses network features as biomarkers to predict survival, and identify new potential therapeutic interventions, thus underscoring the value of analyzing gene regulatory networks in individual cancer patients.

systems biology↗