posted on 2021-12-22, 15:04authored byLea Albert, Jatin Nagpal, Wieland Steinchen, Lei Zhang, Laura Werel, Nemanja Djokovic, Dusan Ruzic, Malte Hoffarth, Jing Xu, Johanna Kaspareit, Frank Abendroth, Antoine Royant, Gert Bange, Katarina Nikolic, Soojin Ryu, Yali Dou, Lars-Oliver Essen, Olalla Vázquez
Optical control has
enabled functional modulation in cell culture
with unparalleled spatiotemporal resolution. However, current tools
for in vivo manipulation are scarce. Here, we design and implement
a genuine on–off optochemical probe capable
of achieving hematopoietic control in zebrafish. Our photopharmacological
approach first developed conformationally strained visible light photoswitches (CS-VIPs) as inhibitors of the histone
methyltransferase MLL1 (KMT2A). In blood homeostasis MLL1 plays a
crucial yet controversial role. CS-VIP 8 optimally fulfils
the requirements of a true bistable functional system in vivo under
visible-light irradiation, and with unprecedented stability. These
properties are exemplified via hematopoiesis photoinhibition with
a single isomer in zebrafish. The present interdisciplinary study
uncovers the mechanism of action of CS-VIPs. Upon WDR5 binding, CS-VIP 8 causes MLL1 release with concomitant allosteric rearrangements
in the WDR5/RbBP5 interface. Since our tool provides on-demand reversible
control without genetic intervention or continuous irradiation, it
will foster hematopathology and epigenetic investigations. Furthermore,
our workflow will enable exquisite photocontrol over other targets
inhibited by macrocycles.