2. Academic Validation
  3. Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

  • ACS Cent Sci. 2022 Jan 26;8(1):57-66. doi: 10.1021/acscentsci.1c00434.
Lea Albert 1,  Jatin Nagpal 2,  Wieland Steinchen 1 3,  Lei Zhang 1,  Laura Werel 1,  Nemanja Djokovic 4,  Dusan Ruzic 4,  Malte Hoffarth 1,  Jing Xu 5,  Johanna Kaspareit 6,  Frank Abendroth 1,  Antoine Royant 7 8,  Gert Bange 1 3,  Katarina Nikolic 4,  Soojin Ryu 6 9 10,  Yali Dou 11,  Lars-Oliver Essen 1 3,  Olalla Vázquez 1 3
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Marburg, 35037 Marburg, Germany.
  • 2 APC Microbiome Ireland, University College Cork, Cork, Ireland.
  • 3 Center for Synthetic Microbiology (SYNMIKRO), University of Marburg, 35037 Marburg, Germany.
  • 4 Department of Pharmaceutical Chemistry, University of Belgrade, 11000 Belgrade, Serbia.
  • 5 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 University Medical Center, Johannes Gutenberg University Mainz, 55122 Mainz, Germany.
  • 7 Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS), 38044 Grenoble, France.
  • 8 European Synchrotron Radiation Facility, 38043 Grenoble, France.
  • 9 Living Systems Institute, University of Exeter, Exeter EX4 QD, U.K.
  • 10 College of Medicine and Health, University of Exeter, Exeter EX4 4PY, U.K.
  • 11 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90007, United States.
PMID: 35106373 DOI: 10.1021/acscentsci.1c00434
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.

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