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Article Dans Une Revue ACS Central Science Année : 2022

Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

Résumé

Optical control has enabled functional modulation in cell culture with unparalleled spatiotemporal resolution. However, current tools for in vivo manipulation are scarce. Her; 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 WDRS binding, CS-VIP 8 causes MLL1 release with concomitant allosteric rearrangements in the WDRS/RbBPS 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.

Domaines

Chimie
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Dates et versions

hal-03621281 , version 1 (13-07-2022)

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Lea Albert, Jatin Nagpal, Wieland Steinchen, Lei Zhang, Laura Werel, et al.. Bistable Photoswitch Allows in Vivo Control of Hematopoiesis. ACS Central Science, 2022, 8 (1), pp.57-66. ⟨10.1021/acscentsci.1c00434⟩. ⟨hal-03621281⟩
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