The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis.

Autor:	Casey MJ; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA., Call AM; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA., Thorpe AV; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA., Jette CA; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA., Engel ME; Department of Pediatric Hematology/Oncology, Emily Couric Cancer Center, University of Virginia, Charlottesville, VA 22903, USA., Stewart RA; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2022 Dec 05; Vol. 26 (1), pp. 105737. Date of Electronic Publication: 2022 Dec 05 (Print Publication: 2023).
DOI:	10.1016/j.isci.2022.105737
Abstrakt:	Lsd1/Kdm1a functions both as a histone demethylase enzyme and as a scaffold for assembling chromatin modifier and transcription factor complexes to regulate gene expression. The relative contributions of Lsd1's demethylase and scaffolding functions during embryogenesis are not known. Here, we analyze two independent zebrafish lsd1/kdm1a mutant lines and show Lsd1 is required to repress primitive hematopoietic stem cell gene expression. Lsd1 rescue constructs containing point mutations that selectively abrogate its demethylase or scaffolding capacity demonstrate the scaffolding function of Lsd1, not its demethylase activity, is required for repression of gene expression in vivo . Lsd1's SNAG-binding domain mediates its scaffolding function and reinforces a negative feedback loop to repress the expression of SNAG-domain-containing genes during embryogenesis, including gfi1 and snai1/2 . Our findings reveal a model in which the SNAG-binding and scaffolding function of Lsd1, and its associated negative feedback loop, provide transient and reversible regulation of gene expression during hematopoietic development. Competing Interests: The authors declare no conflicts of interest. (© 2022 The Author(s).)
Databáze:	MEDLINE
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