Biology subjects

Betschinger, J.

Publications and source records attributed to Betschinger, J..

3 recordsLinked to original sources

bioRxiv2021

WILMS TUMORIGENESIS IN HUMAN KIDNEY ORGANOIDS

The loss or failure of cell differentiation is a hallmark of cancer, yet whether perturbation of differentiation is causal or consequential to malignant transformation is largely unclear. Wilms tumor is the most widespread kidney cancer in children. Here, we establish a model for Wilms tumorigenesis in human kidney organoids. We show that loss of the tumor suppressor WT1 during organoid formation induces overgrowth of kidney progenitor cells at the expense of differentiating tubules. Functional and gene expression analyses demonstrate that absence of WT1 halts progenitor cell progression at a pre-epithelialized cell state and recapitulates the transcriptional changes detected in a subgroup of Wilms tumor patients with ectopic myogenesis. By "transplanting" WT1 mutant cells into wild-type kidney organoids, we find that their propagation requires an untransformed microenvironment. Genetic engineering of cancer lesions in human organoids therefore permits phenotypic modeling of tumor initiation and progression, and complements the current toolbox of pre-clinical Wilms tumor models.

cancer biology↗

bioRxiv2020

A BTB-DOMAIN TRANSCRIPTION FACTOR RECRUITS CHROMATIN REMODELERS AND A HISTONE CHAPERONE DURING THE EXIT FROM PLURIPOTENCY

Transcription factors (TFs) harboring a btb (Broad-Complex, Tramtrack and Bric a brac) domain play important roles in development and disease. They are thought to recruit transcriptional modulators to DNA through their btb domain. However, a systematic molecular understanding of this TF family is lacking. Here, we identify the zinc finger btb-TF Zbtb2 in a genetic screen for regulators of exit from pluripotency and dissect its mechanistic mode of action. We show that ZBTB2 binds the chromatin remodeler Ep400 to mediate downstream transcription. Independently, the btb domain directly interacts with the chromatin remodeller NuRD and the histone chaperone HiRA via the GATAD2A/B and UBN2 subunits, respectively. NuRD recruitment is a common feature of btb-TFs and we propose by phylogenetic analysis that this is an evolutionary ancient property. Binding to UBN2, in contrast, is specific to ZBTB2 and requires a C-terminal extension of the btb domain. This study therefore identifies a btb-domain TF that recruits chromatin modifiers and a histone chaperone during a developmental cell state transition, and defines unique and shared molecular functions of the btb-domain TF family.

molecular biology↗

bioRxiv2020

REPRESSION BY HDAC3 AND DAX1 MEDIATES LINEAGE RESTRICTION OF EMBRYONIC STEM CELLS

Mouse embryonic stem cells (mESCs) give rise to embryonic but not extraembryonic endoderm fates. Here, we identify the mechanism of this lineage barrier and report that the histone deacetylase Hdac3 and the corepressor Dax1 cooperatively restrict transdifferentiation of mESCs by silencing an enhancer of the extraembryonic endoderm-specifying transcription factor (TF) Gata6. This restriction is opposed by the pluripotency TFs Nr5a2 and Esrrb, which promote cell type conversion. Perturbation of the barrier extends mESC potency, and allows formation of 3D spheroids that mimic the spatial segregation of embryonic epiblast and extraembryonic endoderm in early embryos. Overall, this study shows that transcriptional repressors stabilize pluripotency by biasing the equilibrium between embryonic and extraembryonic lineages that is hardwired into the mESC TF network.

developmental biology↗