Biology subjects

Brabletz, T.

Publications and source records attributed to Brabletz, T..

6 recordsLinked to original sources

bioRxiv2025

ZEB1 Is a Key Regulator of Cardiomyocyte Structure and Function

BackgroundOur previous work identified the transcription factor "Zinc Finger E-Box Binding Homeobox 1" (ZEB1) as a downstream effector of Cytoplasmic Polyadenylation Element Binding Protein 4 (CPEB4), an RNA-binding protein responsive to cardiac stress. While ZEB1 is known for its role in cancer metastasis and epithelial-to-mesenchymal transition (EMT), its function in cardiomyocytes is not well understood. Based on previous findings, we hypothesize that ZEB1 is essential for maintaining the structural integrity and mitochondrial function of cardiomyocytes. MethodsAAV9-Zeb1 was used for the overexpression of Zeb1. Using a myosin heavy chain alpha (MHC) Cre system, we created a Zeb1 conditional knockout mouse. To evaluate cardiac function and structure, we used echocardiography, electron microscopy, immunohistochemistry. We identified differentially expressed genes following Zeb1 deletion using RNA-seq and determined direct Zeb1 target genes by integrating this transcriptome data with a Zeb1 ChIP-seq dataset. ResultsZEB1 deletion leads to sarcomere damage, mitochondrial dysfunction, and dedifferentiation, with more pronounced effects in females. Overexpression promotes hypertrophic remodeling. Echocardiographic analysis showed progressive systolic dysfunction, and histology revealed sarcomeric disarray, again especially in females. A tamoxifen-inducible ZEB1 knockout mouse model only confirmed ZEB1s crucial role in fully differentiated cardiomyocytes in female mice. Integrated analysis of RNA-seq and ChIP-seq revealed that Zeb1 directly regulated mitochondrial genes, thereby playing a critical role cardiomyocyte energy supply and having secondary effects on cardiac structure and function. ConclusionsZEB1 is critical for cardiomyocyte homeostasis, and maintaining its function is necessary for normal cardiac performance and structure.

molecular biology↗

bioRxiv2024

Macrophages foster adaptive anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

Tumor-associated macrophages (TAMs) shape the tumor microenvironment (TME) and exert a decisive impact on anti-tumor immunity. Understanding TAM function is therefore critical to understand anti-tumor immune responses and to design immunotherapies. Here, we describe the transcription factor ZEB1, a well-known driver of epithelial-to-mesenchymal transition, as an intrinsic regulator of TAM function in adaptive anti-tumor immunity. By combining cell type-specific deletion of Zeb1 with syngeneic models of colorectal and pancreatic cancer, we discovered an unexpected function of ZEB1 in the TAM-mediated control of T cell trafficking. ZEB1 supports secretion of a subset of chemokines including CCL2 and CCL22 by promoting their transcription and translation as well as by safeguarding protein processing. ZEB1 thereby elevates cytotoxic T cell (CTL) recruitment in vitro and in vivo and fosters immunosurveillance during tumor as well as lung metastatic outgrowth. Our study spotlights ZEB1 as a crucial facilitator of adaptive anti-tumor immunity and uncovers a potential therapeutic window of opportunity for cytokine-guided enhancement of CTL infiltration into tumors and metastases.

cancer biology↗

bioRxiv2023

ZEB1-dependent modulation of fibroblast polarization governs inflammation and immune checkpoint blockade sensitivity in colorectal cancer

The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers is reduced upon fibroblast-specific loss of Zeb1. Single-cell transcriptomics, histological and in vitro characterization reveal a crucial role in CAF polarization, promoting myofibroblastic features whilst restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, pointing to a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.

cancer biology↗

bioRxiv2020

The transcription factor ZEB1 regulates stem cell self-renewal and astroglial fate in the adult hippocampus

Radial glia-like (RGL) cells persist in the adult mammalian hippocampus where they give rise to new neurons and astrocytes throughout life. Many studies have investigated the process of adult neurogenesis, but factors deciding between neuronal and astroglial fate are incompletely understood. Here, we evaluate the functions of the transcription factor zinc finger E-box binding homeobox 1 (ZEB1) in adult hippocampal RGL cells using a conditional-inducible mouse model. We find that ZEB1 is necessary for self-renewal of active RGL cells as well as for astroglial lineage specification. Genetic deletion of Zeb1 causes differentiation-coupled depletion of RGL cells resulting in an increase of newborn neurons at the expense of newly generated astrocytes. This is due to a shift towards symmetric cell divisions that consume the RGL cell and generate pro-neuronal progenies. We identify ZEB1 as a regulator of stem cell self-renewal and lineage specification in the adult hippocampus.

neuroscience↗

bioRxiv2020

Exploration of endogenous miRNA-200b/c activity and regulation through a functional dual fluorescence reporter

Since their discovery, microRNAs (miRNA)s have been widely studied in almost every aspect of biology and medicine, leading to the identification of important gene regulation circuits and cellular mechanisms. However, investigations are generally focused on the analysis of their downstream targets and biological functions in overexpression and knockdown approaches, while miRNAs endogenous levels and activity remain poorly understood. Here, we used the cellular plasticity-regulating process of epithelial-to-mesenchymal transition (EMT) as a model to show the efficacy of a fluorescent sensor to separate cells with distinct EMT signatures, based on miR-200b/c activity. The system was further combined with a CRISPR-Cas9 screening platform to unbiasedly identify miR-200b/c upstream regulating genes. The sensor allows to infer miRNAs fundamental biological properties, as profiling of sorted cells indicated miR-200b/c as a molecular switch between EMT differentiation and proliferation, and suggested a role for metabolic enzymes in miR-200/EMT regulation. Analysis of miRNAs endogenous levels and activity could lead to a better understanding of their biological role in physiology and disease.

molecular biology↗

bioRxiv2018

Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

Aberrant activation of epithelial-mesenchymal transition (EMT) in carcinoma cells contributes to increased migration and invasion, metastasis, drug resistance, and tumor-initiating capacity. EMT is not always a binary process, rather cells may exhibit a hybrid epithelial/mesenchymal (E/M) phenotype. ZEB1 - a key transcription factor driving EMT - can both induce and maintain a mesenchymal phenotype. Recent studies have identified two novel autocrine feedback loops utilizing ESRP1, HAS2, and CD44 that maintain high levels of ZEB1. However, how the crosstalk between these feedback loops alters the dynamics of epithelial-hybrid-mesenchymal transition remains elusive. Here, using an integrated theoretical-experimental framework, we identify that these feedback loops can enable cells to stably maintain a hybrid E/M phenotype. Moreover, computational analysis identifies the regulation of ESRP1 as a crucial node, a prediction that is validated by two complementary experiments showing that (a) overexpression of ESRP1 reverts EMT in MCF10A cells treated with TGF{beta} for 21 days, and (b) knockdown of ESRP1 in stable hybrid E/M H1975 cells drives EMT. Finally, in multiple breast cancer datasets, high levels of ESRP1, ESRP1/HAS2, and ESRP1/ZEB1 correlates with poor prognosis, supporting the relevance of ZEB1/ESRP1 and ZEB1/HAS2 axes in tumor progression. Together, our results unravel how these interconnected feedback loops act in concert to regulate ZEB1 levels and to drive the dynamics of epithelial-hybrid-mesenchymal transition.

cancer biology↗