An in vivo screen of noncoding loci reveals that Daedalus is a gatekeeper of an Ikaros-dependent checkpoint during haematopoiesis
| Autor: | Justin A. Shyer, Rihao Qu, Yuval Kluger, Jorge Henao-Mejia, Ruaidhri Jackson, John L. Rinn, Jun Zhao, Loyal A. Goff, Adam Williams, Louisa Hill, Holly R. Steach, Christian C. D. Harman, Will Bailis, Richard A. Flavell |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 118 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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