PUBLICATION
Bistable Photoswitch Allows in Vivo Control of Hematopoiesis
- Authors
- Albert, L., Nagpal, J., Steinchen, W., Zhang, L., Werel, L., Djokovic, N., Ruzic, D., Hoffarth, M., Xu, J., Kaspareit, J., Abendroth, F., Royant, A., Bange, G., Nikolic, K., Ryu, S., Dou, Y., Essen, L.O., Vázquez, O.
- ID
- ZDB-PUB-220203-2
- Date
- 2022
- Source
- ACS central science 8: 57-66 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 35106373 Full text @ ACS Cent Sci
Citation
Albert, L., Nagpal, J., Steinchen, W., Zhang, L., Werel, L., Djokovic, N., Ruzic, D., Hoffarth, M., Xu, J., Kaspareit, J., Abendroth, F., Royant, A., Bange, G., Nikolic, K., Ryu, S., Dou, Y., Essen, L.O., Vázquez, O. (2022) Bistable Photoswitch Allows in Vivo Control of Hematopoiesis. ACS central science. 8:57-66.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping