Biology subjects

Calonghi, N.

Publications and source records attributed to Calonghi, N..

2 recordsLinked to original sources

bioRxiv2022

Expanding the HDAC druggable landscape beyond enzymatic inhibition

Enzymatic pockets such as those of histone deacetylases (HDACs) are among the most favored targets for drug development. However, enzymatic inhibitors often exhibit low selectivity and high toxicity due to targeting multiple enzyme paralogs, which are often involved in distinct multisubunit complexes. Here, we report the discovery and characterization of a non-enzymatic small molecule inhibitor of HDAC transcriptional repression functions with comparable anti-tumor activity to the enzymatic HDAC inhibitor Vorinostat, and anti-psychedelic activity of an HDAC2 knockout in vivo. We highlight that these phenotypes are achieved while modulating the expression of 20- and 80-fold fewer genes than enzymatic and genetic inhibition in the respective models. Thus, by achieving the same biological outcomes as established therapeutics while impacting a dramatically smaller number of genes, inhibitors of protein-protein interactions can offer important advantages in improving the selectivity of epigenetic modulators. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/519454v2_ufig1.gif" ALT="Figure 1"> View larger version (96K): org.highwire.dtl.DTLVardef@3a4e68org.highwire.dtl.DTLVardef@1f1be2corg.highwire.dtl.DTLVardef@1fc5e94org.highwire.dtl.DTLVardef@1a54790_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2019

Redox signaling via lipid peroxidation regulates retinal progenitor cell differentiation

Reactive oxygen species (ROS) and downstream products of lipid oxidation are emerging as important secondary messengers in tissue homeostasis. However their regulation and mechanism of action remain poorly studied in vivo during normal development. Here we reveal that the fine regulation of hydrogen peroxide (H2O2) levels at the degradation step by its scavenger Catalase is crucial to mediate the switch from proliferation to differentiation in retinal progenitor cells (RPCs). We further show that altering the levels of downstream products of the Redox signaling can also affect this switch. Indeed, we identify 9-hydroxystearic acid (9-HSA), an endogenous downstream lipid peroxidation product, as a mediator of this effect in the zebrafish retina. In fact, RPCs exposed to higher amounts of 9-HSA failed to differentiate and remained proliferative. We found that 9-HSA exerts its biological function in vivo by inhibiting the activity of histone deacetylase 1. We finally show that the local and temporal manipulation of H2O2 levels by catalase overexpression in RPCs was sufficient to trigger their premature differentiation. Therefore the amount of H2O2 in RPCs is instructive of their ability to switch from proliferation to differentiation. We propose a mechanism that acts in RPC and linking H2O2 homeostasis and neuronal differentiation via the modulation of lipid peroxidation.

developmental biology↗