Biology subjects

Stoetzel, M.

Publications and source records attributed to Stoetzel, M..

4 recordsLinked to original sources

bioRxiv2026

Nuclear mTOR-Polycomb synergism at developmental gene promoters prone to activation

Pluripotent cells hold the capacity to differentiate into cells with diverse functions, enabling development and regeneration. The balance between local epigenetic repression and maintaining the potential for prompt transcriptional activation supports pluripotency while allowing imminent differentiation. How the activation of developmental pathways is correctly timed in sync with the environment remains poorly understood. Here we find that the cellular growth regulator mTOR selectively binds developmental gene promoters in pluripotent mouse embryonic stem cells. mTOR binding at target genes correlates with and depends on histone H2AK119 monoubiquitination (H2AK119ub1) deposited by the Polycomb Repressor Complex 1 (PRC1). Acute depletion of the whole PRC1 complex or its catalytic activity leads to depletion of mTOR at target gene promoters, whereas forced PRC1 recruitment to an artificial site brings along mTOR. At target genes, mTOR colocalizes with components of the transcription machinery and we find that mTOR-bound genes are distinctly characterized by high levels of RNA Polymerase II pausing. Our findings reveal a role of mTOR in pluripotency regulation and highlight the tight crosstalk between gene regulatory and cell growth machineries in stem cells.

molecular biology↗

bioRxiv2022

Metabolic enhancement of mammalian developmental pausing

The quest to model and modulate embryonic development became a recent cornerstone of stem cell and developmental biology. Mammalian developmental timing is adjustable in vivo by preserving preimplantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet constraints to pause duration are unrecognized. By comparing the response of embryonic and extraembryonic stem cells to mTORi-induced pausing, we identified lipid usage as a bottleneck to developmental pausing. Enhancing fatty acid oxidation (FAO) boosts embryo longevity, while blocking it reduces the pausing capacity. Genomic and metabolic analyses of single embryos point toward a deeper dormant state in FAO-enhanced pausing and reveal a link between lipid metabolism and embryo morphology. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues. One-Sentence SummaryFacilitating fatty acid oxidation by carnitine supplementation enhances mTOR inhibition-mediated developmental pausing.

developmental biology↗

bioRxiv2022

GATA transcription factors drive initial Xist upregulation after fertilization through direct activation of a distal enhancer element

To ensure dosage compensation for X-linked genes between the sexes, one X chromosome is silenced during early embryonic development of female mammals. This process of X-chromosome inactivation (XCI) is initiated through upregulation of the RNA Xist from one X chromosome shortly after fertilization. Xist then mediates chromosome-wide gene silencing in cis and remains expressed in all cell types except the germ line and the pluripotent state, where XCI is reversed. The factors that drive Xist upregulation and thereby initiate XCI remain however unknown. We identify GATA transcription factors as potent Xist activators and demonstrate that they are essential for the activation of Xist in mice following fertilization. Through a pooled CRISPR activation screen we find that GATA1 can drive ectopic Xist expression in murine embryonic stem cells (mESCs). We demonstrate that all GATA factors can activate Xist directly via a GATA-responsive regulatory element (RE79) positioned 100 kb upstream of the Xist promoter. Additionally, GATA factors are essential for the induction of XCI in mouse preimplantation embryos, as simultaneous deletion of three members of the GATA family (GATA1/4/6) in mouse zygotes effectively prevents Xist upregulation. Thus, initiation of XCI and possibly its maintenance in distinct lineages of the preimplantation embryo is ensured by the combined activity of different GATA family members, and the absence of GATA factors in the pluripotent state likely contributes to X reactivation. We thus describe a form of regulation in which the combined action of numerous tissue-specific factors can achieve near-ubiquitous expression of a target gene.

genetics↗

bioRxiv2019

Posttranscriptional regulation of ribosomal and multiresistance genes by the bacterial leader peptide peTrpL

The ribosome-dependent attenuator located upstream of bacterial tryptophan biosynthesis genes harbors a small ORF trpL containing tryptophan codons. When tryptophan is available, efficient trpL translation causes transcription termination and release of the attenuator RNA rnTrpL. In Sinorhizobium meliloti, rnTrpL is a trans-acting sRNA. Here, we identified an evolutionary conserved function for the trpL-encoded 14-aa leader peptide peTrpL. Upon exposure to tetracycline, the cellular peTrpL levels were increased and rnTrpL was generated independently of tryptophan availability. Both peTrpL and rnTrpL were found to be involved in tetracycline-dependent destabilization of rplUrpmA mRNA encoding ribosomal proteins L21 and L27. We provide evidence for redirection of the sRNA rnTrpL from its antibiotic-independent target trpDC to rplUrpmA by formation of an antibiotic-dependent ribonucleoprotein complex (ARNP). ARNPs comprising peTrpL, rnTrpL, rplUrpmA and antisense RNA were also observed for other translation-inhibiting antibiotics, suggesting that bacteria evolved mechanisms to utilize antibiotics for mRNA destabilization.

microbiology↗