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

Autor:	Harman CCD; Department of Genetics, Yale School of Medicine, New Haven, CT 06520.; Howard Hughes Medical Institute, New Haven, CT 06520., Bailis W; Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104.; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104., Zhao J; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Department of Pathology, Yale School of Medicine, New Haven, CT 06510.; Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520., Hill L; Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria., Qu R; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Department of Pathology, Yale School of Medicine, New Haven, CT 06510.; Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520., Jackson RP; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520., Shyer JA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520., Steach HR; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520., Kluger Y; Department of Pathology, Yale School of Medicine, New Haven, CT 06510.; Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520.; Applied Mathematics Program, Yale University, New Haven, CT 06511., Goff LA; Broad Institute of MIT and Harvard, Cambridge, MA 02142.; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205., Rinn JL; Broad Institute of MIT and Harvard, Cambridge, MA 02142.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02115.; Department of Biochemistry, University of Colorado, BioFrontiers Institute, Boulder, CO 80301., Williams A; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032.; Department of Genetics and Genomic Sciences, University of Connecticut Health Center, Farmington, CT 06030., Henao-Mejia J; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104., Flavell RA; Howard Hughes Medical Institute, New Haven, CT 06520; richard.flavell@yale.edu.; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jan 19; Vol. 118 (3).
DOI:	10.1073/pnas.1918062118
Abstrakt:	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. Competing Interests: Competing interest statement: R.A.F. is a consultant for GSK and Zai Lab Ltd.
Databáze:	MEDLINE
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