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Contributed by Richard A. Flavell, December 7, 2020 (sent for review December 5, 2019; reviewed by Cornelis Murre and Ellen V. Rothenberg)
Significance
The development of lymphocytes is critical for host immunity and relies on a series of developmental checkpoints regulated by key transcription factors such as Ikaros. We hypothesized that nonprotein-coding loci might represent an additional layer of control in lymphocyte development. We identified a noncoding region (Daedalus) whose absence leads to a profound loss of Ikaros protein and a severe reduction in early lymphocyte progenitors. In contrast to Ikaros deletion, removal of Daedalus also led to an increase in red-blood-cell colony formation, suggesting that Daedalus functions as a lineage-specific stabilizer of Ikaros activity, thus acting as a “gatekeeper” of a newly identified lymphoid-erythroid checkpoint. This finding presents a paradigm potentially applicable to the control of all developmental programs.
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.
Footnotes
↵1C.C.D.H. and W.B. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: richard.flavell{at}yale.edu.
Author contributions: C.C.D.H., W.B., R.P.J., L.A.G., J.L.R., A.W., J.H.-M., and R.A.F. designed research; R.A.F. supervised the research and edited the manuscript; C.C.D.H., W.B., L.H., R.P.J., J.A.S., H.R.S., L.A.G., J.L.R., A.W., and J.H.-M. performed research; J.Z., R.Q., and Y.K. contributed new reagents/analytic tools; C.C.D.H., W.B., J.Z., L.H., R.Q., R.P.J., J.A.S., H.R.S., Y.K., L.A.G., J.L.R., and R.A.F. analyzed data; and C.C.D.H. and W.B. wrote the paper.
Reviewers: C.M., University of California San Diego; and E.V.R., California Institute of Technology.
Competing interest statement: R.A.F. is a consultant for GSK and Zai Lab Ltd.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1918062118/-/DCSupplemental.
Data Availability.
All sequencing data for this study was uploaded to the Gene Expression Omnibus (GEO) repository under accession superseries GSE153879 unless otherwise specified. Hi-C sequencing data for this study is available at the GEO repository under the accession nos. GSM4350200 and GSM4350198 (in GSE140975) and was published in Hill et al. (52).
Published under the PNAS license.
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An in vivo screen of noncoding loci reveals that Daedalus is a gatekeeper of an Ikaros-dependent checkpoint during haematopoiesis
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