Deleting an Nr4a1 Super-Enhancer Subdomain Ablates Ly6Clow Monocytes while Preserving Macrophage Gene Function

Graham D. Thomas, Richard N. Hanna, Neelakatan T. Vasudevan, Anouk A. Hamers, Casey E. Romanoski, Sara McArdle, Kevin D. Ross, Amy Blatchley, Deborah Yoakum, Bruce A. Hamilton, Zbigniew Mikulski, Mukesh K. Jain, Christopher K. Glass, Catherine C. Hedrick

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Mononuclear phagocytes are a heterogeneous family that occupy all tissues and assume numerous roles to support tissue function and systemic homeostasis. Our ability to dissect the roles of individual subsets is limited by a lack of technologies that ablate gene function within specific mononuclear phagocyte sub-populations. Using Nr4a1-dependent Ly6Clow monocytes, we present a proof-of-principle approach that addresses these limitations. Combining ChIP-seq and molecular approaches we identified a single, conserved, sub-domain within the Nr4a1 enhancer that was essential for Ly6Clow monocyte development. Mice lacking this enhancer lacked Ly6Clow monocytes but retained Nr4a1 gene expression in macrophages during steady state and in response to LPS. Because Nr4a1 regulates inflammatory gene expression and differentiation of Ly6Clow monocytes, decoupling these processes allows Ly6Clow monocytes to be studied independently.

Original languageEnglish (US)
Pages (from-to)975-987
Number of pages13
JournalImmunity
Volume45
Issue number5
DOIs
StatePublished - Nov 15 2016
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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