The homeobox transcription factor DUXBL controls exit from totipotency
In mice, exit from the totipotent two-cell (2C) stage embryo requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here we demonstrate that the 2C-specific transcription factor double homeobox protein (DU...
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Published in | Nature genetics Vol. 56; no. 4; pp. 697 - 709 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Nature Publishing Group
01.04.2024
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Subjects | |
Online Access | Get full text |
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Summary: | In mice, exit from the totipotent two-cell (2C) stage embryo requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here we demonstrate that the 2C-specific transcription factor double homeobox protein (DUX) mediates an essential negative feedback loop by inducing the expression of DUXBL to promote this silencing. We show that DUXBL gains accessibility to DUX-bound regions specifically upon DUX expression. Furthermore, we determine that DUXBL interacts with TRIM24 and TRIM33, members of the TRIM superfamily involved in gene silencing, and colocalizes with them in nuclear foci upon DUX expression. Importantly, DUXBL overexpression impairs 2C-associated transcription, whereas Duxbl inactivation in mouse embryonic stem cells increases DUX-dependent induction of the 2C-transcriptional program. Consequently, DUXBL deficiency in embryos results in sustained expression of 2C-associated transcripts leading to early developmental arrest. Our study identifies DUXBL as an essential regulator of totipotency exit enabling the first divergence of cell fates. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors jointly supervised this work AUTHOR CONTRIBUTIONS M.V-S., F.F.L., T.O., J.K. and S.R. conceived the study. T.O., M.V-S. and F.F.L., designed, performed, and analyzed most of in vitro experiments. Y.C., J.Z., T.L. and L.S. designed and performed experiments. K.-P.K. and H.S. provided vectors. P.S., V.S., and L.R. performed microinjection and in vivo experiments. C.N.D. provided technical support. S.G. and D.T. analyzed sequencing data. C.K. and M.B. analyzed data and performed bioinformatic analyses under the supervision of M.L. G.I.C. provided support with high-throughput microscopy imaging. B.S. analyzed live confocal microscopy data. T.K.M. and L.M.J. performed and analyzed Mass Spectrometry experiments. D.B. and M.K. provided critical input. S.R., J.K. and C.J.W. supervised the study and wrote the manuscript with comments and help from all authors. These authors contributed equally |
ISSN: | 1061-4036 1546-1718 1546-1718 |
DOI: | 10.1038/s41588-024-01692-z |