PU.1-c-Jun Interaction is Crucial for PU.1 Function in Myeloid Development

Overview

Journal Commun Biol

Specialty Biology

Date 2022 Sep 14

PMID 36104445

Authors

Xinhui Zhao

Boris Bartholdy

Yukiya Yamamoto

Erica K Evans

Meritxell Alberich-Jorda

Philipp B Staber

Touati Benoukraf

Pu Zhang

Junyan Zhang

Bon Q Trinh

John D Crispino

Trang Hoang

Mahmoud A Bassal

Daniel G Tenen

Affiliations

Soon will be listed here.

Abstract

The Ets transcription factor PU.1 is essential for inducing the differentiation of monocytes, macrophages, and B cells in fetal liver and adult bone marrow. PU.1 controls hematopoietic differentiation through physical interactions with other transcription factors, such as C/EBPα and the AP-1 family member c-Jun. We found that PU.1 recruits c-Jun to promoters without the AP-1 binding sites. To address the functional importance of this interaction, we generated PU.1 point mutants that do not bind c-Jun while maintaining normal DNA binding affinity. These mutants lost the ability to transactivate a target reporter that requires a physical PU.1-c-Jun interaction, and did not induce monocyte/macrophage differentiation of PU.1-deficient cells. Knock-in mice carrying these point mutations displayed an almost complete block in hematopoiesis and perinatal lethality. While the PU.1 mutants were expressed in hematopoietic stem and early progenitor cells, myeloid differentiation was severely blocked, leading to an almost complete loss of mature hematopoietic cells. Differentiation into mature macrophages could be restored by expressing PU.1 mutant fused to c-Jun, demonstrating that a physical PU.1-c-Jun interaction is crucial for the transactivation of PU.1 target genes required for myeloid commitment and normal PU.1 function in vivo during macrophage differentiation.

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