Biology subjects

Druffel-Augustin, S.

Publications and source records attributed to Druffel-Augustin, S..

3 recordsLinked to original sources

bioRxiv2026

Essential genes are dominantly activated by single transcription factors

Cell viability depends on the precise expression of essential genes, which are controlled by CpG-island (CGI) promoters densely bound by transcription factors (TFs). This has led to the prevailing model that TFs cooperate to ensure ubiquitous expression. Here, using rapid and reversible single and combinatorial degradation in murine stem cells, we systematically dissect the regulatory interactions between five key TFs. We uncover an unexpectedly specific architecture in which regulatory dominance, rather than cooperation, is the prevailing mode, where individual TFs autonomously drive chromatin opening and gene activation at largely distinct promoters. Cooperative regulation occurs at a minority of sites with antagonistic or synergistic outcomes modulated by the interplay between nucleosome positioning and TF sensitivity to chromatin. This logic is recapitulated at synthetic sequences and reflected in human genetic variation. These findings reveal that single TFs dominantly activate distinct sets of CGI-linked genes, including essential genes, across development, homeostasis, and disease.

molecular biology↗

bioRxiv2022

Dissecting aggregation and seeding dynamics of α-Syn polymorphs using the phasor approach to FLIM

Synucleinopathies are a heterogenous group of neurodegenerative diseases characterized by the progressive accumulation of pathological -synuclein (-Syn). The importance of structural polymorphism of -Syn assemblies for distinct synucleinopathies and their progression is increasingly recognized. However, the underlying mechanisms are poorly understood. Here we use fluorescence lifetime imaging microscopy (FLIM) to investigate seeded aggregation of -Syn in a biosensor cell line. We show that conformationally distinct -Syn polymorphs exhibit characteristic fluorescence lifetimes. FLIM further revealed that -Syn polymorphs were differentially processed by cellular clearance pathways, yielding fibrillar species with increased seeding capacity. Thus, FLIM is not only a powerful tool to distinguish different amyloid structures, but also to monitor the dynamic process of amyloid remodeling by the cellular environment. Our data suggest that the accumulation of highly seeding competent degradation products for particular polymorphs may account for accelerated disease progression in some patients.

molecular biology↗

bioRxiv2019

HSP110 dependent HSP70 disaggregation machinery mediates prion-like propagation of amyloidogenic proteins in metazoa

The gradual accumulation and prion-like propagation of -synuclein and other amyloidogenic proteins is associated with devastating neurodegenerative diseases. The metazoan disaggregation machinery, a specific combination of HSP70 and its co-chaperones, is able to disassemble -synuclein fibrils in vitro, but the physiological consequence in vivo is unknown. To explore this, we used Caenorhabditis elegans models that exhibit pathological features of -synuclein, such as misfolding, intercellular spreading and toxicity. We inhibited the HSP70 disaggregase by depleting the crucial component HSP-110 and monitored the effect on -synuclein related phenotypes. The knockdown of HSP-110 not only impaired HSP70 disaggregation activity and prevented the resolubilization of amorphous heat shock induced firefly luciferase aggregates, but also compromised the cellular folding capacity. In stark contrast, HSP-110 depletion reduced -synuclein foci formation, cell-to-cell transmission and toxicity. Similar effects were observed for a polyQ model substrate, confirming that inhibition of HSP70 disaggregation function mitigates amyloid toxicity. These data demonstrate that the metazoan HSP70 disaggregation complex plays a critical role in the prion-like propagation of amyloid-type conformers. Therefore, the HSP70 disaggregation activity is a double-edged sword as it is essential for the maintenance of cellular proteostasis while being involved in the generation of toxic amyloid-type protein species.

cell biology↗