Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

Lea 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

doi:10.1021/acscentsci.1c00434

Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

Lea 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	57-66
Number of pages	10
Journal	ACS Central Science
Volume	8
Issue number	1
DOIs	https://doi.org/10.1021/acscentsci.1c00434
Publication status	Published - 26 Jan 2022

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10.1021/acscentsci.1c00434

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title = "Bistable Photoswitch Allows in Vivo Control of Hematopoiesis",

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.",

author = "Lea Albert and Jatin Nagpal and Wieland Steinchen and Lei Zhang and Laura Werel and Nemanja Djokovic and Dusan Ruzic and Malte Hoffarth and Jing Xu and Johanna Kaspareit and Frank Abendroth and Antoine Royant and Gert Bange and Katarina Nikolic and Soojin Ryu and Yali Dou and Essen, \{Lars Oliver\} and Olalla V{\'a}zquez",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society",

year = "2022",

month = jan,

day = "26",

doi = "10.1021/acscentsci.1c00434",

language = "English",

volume = "8",

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T1 - Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

AU - Albert, Lea

AU - Nagpal, Jatin

AU - Steinchen, Wieland

AU - Zhang, Lei

AU - Werel, Laura

AU - Djokovic, Nemanja

AU - Ruzic, Dusan

AU - Hoffarth, Malte

AU - Xu, Jing

AU - Kaspareit, Johanna

AU - Abendroth, Frank

AU - Royant, Antoine

AU - Bange, Gert

AU - Nikolic, Katarina

AU - Ryu, Soojin

AU - Dou, Yali

AU - Essen, Lars Oliver

AU - Vázquez, Olalla

PY - 2022/1/26

Y1 - 2022/1/26

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85122339027

U2 - 10.1021/acscentsci.1c00434

DO - 10.1021/acscentsci.1c00434

M3 - Article

AN - SCOPUS:85122339027

SN - 2374-7943

VL - 8

SP - 57

EP - 66

JO - ACS Central Science

JF - ACS Central Science

IS - 1

ER -

Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

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