DUX4 is a multifunctional factor priming human embryonic genome activation

Sanna Vuoristo; Shruti Bhagat; Christel Hydén-Granskog; Masahito Yoshihara; Lisa Gawriyski; Eeva-Mari Jouhilahti; Vipin Ranga; Mahlet Tamirat; Mikko Huhtala; Ida Kirjanov; Sonja Nykänen; Kaarel Krjutškov; Anastassius Damdimopoulos; Jere Weltner; Kosuke Hashimoto; Gaëlle Recher; Sini Ezer; Priit Paluoja; Pauliina Paloviita; Yujiro Takegami; Ai Kanemaru; Karolina Lundin; Tomi T Airenne; Timo Otonkoski; Juha S Tapanainen; Hideya Kawaji; Yasuhiro Murakawa; Thomas R Bürglin; Markku Varjosalo; Mark S Johnson; Timo Tuuri; Shintaro Katayama; Juha Kere

doi:10.1016/j.isci.2022.104137

DUX4 is a multifunctional factor priming human embryonic genome activation

Sanna Vuoristo, Shruti Bhagat, Christel Hydén-Granskog, Masahito Yoshihara, Lisa Gawriyski, Eeva-Mari Jouhilahti, Vipin Ranga, Mahlet Tamirat, Mikko Huhtala, Ida Kirjanov, Sonja Nykänen, Kaarel Krjutškov, Anastassius Damdimopoulos, Jere Weltner, Kosuke Hashimoto, Gaëlle Recher, Sini Ezer, Priit Paluoja, Pauliina Paloviita, Yujiro TakegamiAi Kanemaru, Karolina Lundin, Tomi T Airenne, Timo Otonkoski, Juha S Tapanainen, Hideya Kawaji, Yasuhiro Murakawa, Thomas R Bürglin, Markku Varjosalo, Mark S Johnson, Timo Tuuri, Shintaro Katayama, Juha Kere

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Abstract

Double homeobox 4 (DUX4) is expressed at the early pre-implantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the chromatin accessibility of non-coding DNA and activates thousands of newly identified transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome.

Original language	English
Article number	104137
Number of pages	29
Journal	iScience
Volume	25
Issue number	4
DOIs	https://doi.org/10.1016/j.isci.2022.104137
Publication status	Published - 15 Apr 2022
MoE publication type	A1 Journal article-refereed

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10.1016/j.isci.2022.104137Licence: CC BY

1-s2.0-S2589004222004072-mainFinal published version, 4.11 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe2023030329399

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Vuoristo, S., Bhagat, S., Hydén-Granskog, C., Yoshihara, M., Gawriyski, L., Jouhilahti, E.-M., Ranga, V., Tamirat, M., Huhtala, M., Kirjanov, I., Nykänen, S., Krjutškov, K., Damdimopoulos, A., Weltner, J., Hashimoto, K., Recher, G., Ezer, S., Paluoja, P., Paloviita, P., ... Kere, J. (2022). DUX4 is a multifunctional factor priming human embryonic genome activation. iScience, 25(4), Article 104137. https://doi.org/10.1016/j.isci.2022.104137

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title = "DUX4 is a multifunctional factor priming human embryonic genome activation",

abstract = "Double homeobox 4 (DUX4) is expressed at the early pre-implantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the chromatin accessibility of non-coding DNA and activates thousands of newly identified transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome.",

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author = "Sanna Vuoristo and Shruti Bhagat and Christel Hyd{\'e}n-Granskog and Masahito Yoshihara and Lisa Gawriyski and Eeva-Mari Jouhilahti and Vipin Ranga and Mahlet Tamirat and Mikko Huhtala and Ida Kirjanov and Sonja Nyk{\"a}nen and Kaarel Krjut{\v s}kov and Anastassius Damdimopoulos and Jere Weltner and Kosuke Hashimoto and Ga{\"e}lle Recher and Sini Ezer and Priit Paluoja and Pauliina Paloviita and Yujiro Takegami and Ai Kanemaru and Karolina Lundin and Airenne, {Tomi T} and Timo Otonkoski and Tapanainen, {Juha S} and Hideya Kawaji and Yasuhiro Murakawa and B{\"u}rglin, {Thomas R} and Markku Varjosalo and Johnson, {Mark S} and Timo Tuuri and Shintaro Katayama and Juha Kere",

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Vuoristo, S, Bhagat, S, Hydén-Granskog, C, Yoshihara, M, Gawriyski, L, Jouhilahti, E-M, Ranga, V, Tamirat, M, Huhtala, M, Kirjanov, I, Nykänen, S, Krjutškov, K, Damdimopoulos, A, Weltner, J, Hashimoto, K, Recher, G, Ezer, S, Paluoja, P, Paloviita, P, Takegami, Y, Kanemaru, A, Lundin, K, Airenne, TT, Otonkoski, T, Tapanainen, JS, Kawaji, H, Murakawa, Y, Bürglin, TR, Varjosalo, M, Johnson, MS, Tuuri, T, Katayama, S & Kere, J 2022, 'DUX4 is a multifunctional factor priming human embryonic genome activation', iScience, vol. 25, no. 4, 104137. https://doi.org/10.1016/j.isci.2022.104137

TY - JOUR

T1 - DUX4 is a multifunctional factor priming human embryonic genome activation

AU - Vuoristo, Sanna

AU - Bhagat, Shruti

AU - Hydén-Granskog, Christel

AU - Yoshihara, Masahito

AU - Gawriyski, Lisa

AU - Jouhilahti, Eeva-Mari

AU - Ranga, Vipin

AU - Tamirat, Mahlet

AU - Huhtala, Mikko

AU - Kirjanov, Ida

AU - Nykänen, Sonja

AU - Krjutškov, Kaarel

AU - Damdimopoulos, Anastassius

AU - Weltner, Jere

AU - Hashimoto, Kosuke

AU - Recher, Gaëlle

AU - Ezer, Sini

AU - Paluoja, Priit

AU - Paloviita, Pauliina

AU - Takegami, Yujiro

AU - Kanemaru, Ai

AU - Lundin, Karolina

AU - Airenne, Tomi T

AU - Otonkoski, Timo

AU - Tapanainen, Juha S

AU - Kawaji, Hideya

AU - Murakawa, Yasuhiro

AU - Bürglin, Thomas R

AU - Varjosalo, Markku

AU - Johnson, Mark S

AU - Tuuri, Timo

AU - Katayama, Shintaro

AU - Kere, Juha

PY - 2022/4/15

Y1 - 2022/4/15

N2 - Double homeobox 4 (DUX4) is expressed at the early pre-implantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the chromatin accessibility of non-coding DNA and activates thousands of newly identified transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome.

AB - Double homeobox 4 (DUX4) is expressed at the early pre-implantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the chromatin accessibility of non-coding DNA and activates thousands of newly identified transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome.

KW - InFlames

U2 - 10.1016/j.isci.2022.104137

DO - 10.1016/j.isci.2022.104137

M3 - Article

C2 - 35402882

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 4

M1 - 104137

ER -

DUX4 is a multifunctional factor priming human embryonic genome activation

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