Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

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.; Vazquez, O.

doi:10.1021/acscentsci.1c00434

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Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

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https://www.ncbi.nlm.nih.gov/pubmed/35106373
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Albert, L., Nagpal, J., Steinchen, W., Zhang, L., Werel, L., Djokovic, N., et al. (2022). Bistable Photoswitch Allows in Vivo Control of Hematopoiesis. ACS Central Science, 8(1), 57-66. doi:10.1021/acscentsci.1c00434.

Cite as: https://hdl.handle.net/21.11116/0000-000A-26E5-9

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.