An in vivo screen of noncoding loci reveals that Daedalus is a gatekeeper of an Ikaros-dependent checkpoint during haematopoiesis

Christian C.D. Harman, Will Bailis, Jun Zhao, Louisa Hill, Rihao Qu, Ruaidhrí P. Jackson, Justin A. Shyer, Holly R. Steach, Yuval Kluger, Loyal A. Goff, John L. Rinn, Adam Williams, Jorge Henao-Mejia, Richard A. Flavell

Research output: Contribution to journalArticlepeer-review

Abstract

Haematopoiesis relies on tightly controlled gene expression patterns as development proceeds through a series of progenitors. While the regulation of hematopoietic development has been well studied, the role of noncoding elements in this critical process is a developing field. In particular, the discovery of new regulators of lymphopoiesis could have important implications for our understanding of the adaptive immune system and disease. Here we elucidate how a noncoding element is capable of regulating a broadly expressed transcription factor, Ikaros, in a lymphoid lineage-specific manner, such that it imbues Ikaros with the ability to specify the lymphoid lineage over alternate fates. Deletion of the Daedalus locus, which is proximal to Ikaros, led to a severe reduction in early lymphoid progenitors, exerting control over the earliest fate decisions during lymphoid lineage commitment. Daedalus locus deletion led to alterations in Ikaros isoform expression and a significant reduction in Ikaros protein. The Daedalus locus may function through direct DNA interaction as Hi-C analysis demonstrated an interaction between the two loci. Finally, we identify an Ikaros-regulated erythroid-lymphoid checkpoint that is governed by Daedalus in a lymphoid-lineage-specific manner. Daedalus appears to act as a gatekeeper of Ikaros's broad lineage-specifying functions, selectively stabilizing Ikaros activity in the lymphoid lineage and permitting diversion to the erythroid fate in its absence. These findings represent a key illustration of how a transcription factor with broad lineage expression must work in concert with noncoding elements to orchestrate hematopoietic lineage commitment.

Original languageEnglish (US)
Article numbere1918062118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number3
DOIs
StatePublished - Jan 14 2021

Keywords

  • Hematopoiesis
  • Ikaros
  • Lymphocytes
  • Noncoding

ASJC Scopus subject areas

  • General

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