Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Yulia Kargapolova; Rizwan Rehimi; Hülya Kayserili; Joanna Brühl; Konstantinos Sofiadis; Anne Zirkel; Spiros Palikyras; Athanasia Mizi; Yun Li; Gökhan Yigit; Alexander Hoischen; Stefan Frank; Nicole Russ; Jonathan Trautwein; Bregje van Bon; Christian Gilissen; Magdalena Laugsch; Eduardo Gade Gusmao; Natasa Josipovic; Janine Altmüller; Peter Nürnberg; Gernot Längst; Frank J. Kaiser; Erwan Watrin; Han Brunner; Alvaro Rada-Iglesias; Leo Kurian; Bernd Wollnik; Karim Bouazoune; Argyris Papantonis

doi:10.1038/s41467-021-23327-1

Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Yulia Kargapolova^*, Rizwan Rehimi, Hülya Kayserili, Joanna Brühl, Konstantinos Sofiadis, Anne Zirkel, Spiros Palikyras, Athanasia Mizi, Yun Li, Gökhan Yigit, Alexander Hoischen, Stefan Frank, Nicole Russ, Jonathan Trautwein, Bregje van Bon, Christian Gilissen, Magdalena Laugsch, Eduardo Gade Gusmao, Natasa Josipovic, Janine AltmüllerPeter Nürnberg, Gernot Längst, Frank J. Kaiser, Erwan Watrin, Han Brunner, Alvaro Rada-Iglesias, Leo Kurian, Bernd Wollnik, Karim Bouazoune, Argyris Papantonis

^*Corresponding author for this work

17 Citations (Scopus)

Abstract

Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.

Original language	English
Article number	3014
Journal	Nature Communications
Volume	12
Issue number	1
Pages (from-to)	3014
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-021-23327-1
Publication status	Published - 21.05.2021

Funding

We would like to thank all members of the Papantonis, Kurian, Rada-Iglesias, and Wollnik laboratories for helpful discussions, Ioanna Papadionysiou for help with ChIP, and Alexander Brehm for critical reading of the manuscript. We also thank the CMMC Imaging and Cell Sorting facilities, the CECAD Proteomics facility, the Cologne Center for Genomics, the High-Performance Computing cluster “CHEOPS” of the University of Cologne for continuous access to resources, as well as Anastassis Perrakis and Alexander Fish for help with nanoDSF aggregation profiles via the iNEXT-Discovery project 12215. We are thankful to the Baldus and Winkels labs for support and access to the Cytek instrument. This work was supported by UKGM (Project 5/2016), by the Deutsche Forschungsgemeinschaft via TRR81 (Project 109546710) and CCRC2407 (Project 360043781), as well as by an Else-Kroener-Fresenius-Stiftung “Key-Project” grant (Project 2015_A125). Y.K. was further supported by the TRR259 (Project 397484323), and S.P. and N.J. by the International Max Planck Research School for Genome Science, part of the GAUSS/GGNB.

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Research Area: Medical Genetics

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Kargapolova, Y., Rehimi, R., Kayserili, H., Brühl, J., Sofiadis, K., Zirkel, A., Palikyras, S., Mizi, A., Li, Y., Yigit, G., Hoischen, A., Frank, S., Russ, N., Trautwein, J., van Bon, B., Gilissen, C., Laugsch, M., Gusmao, E. G., Josipovic, N., ... Papantonis, A. (2021). Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. Nature Communications, 12(1), 3014. Article 3014. https://doi.org/10.1038/s41467-021-23327-1

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abstract = "Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.",

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Kargapolova, Y, Rehimi, R, Kayserili, H, Brühl, J, Sofiadis, K, Zirkel, A, Palikyras, S, Mizi, A, Li, Y, Yigit, G, Hoischen, A, Frank, S, Russ, N, Trautwein, J, van Bon, B, Gilissen, C, Laugsch, M, Gusmao, EG, Josipovic, N, Altmüller, J, Nürnberg, P, Längst, G, Kaiser, FJ, Watrin, E, Brunner, H, Rada-Iglesias, A, Kurian, L, Wollnik, B, Bouazoune, K & Papantonis, A 2021, 'Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology', Nature Communications, vol. 12, no. 1, 3014, pp. 3014. https://doi.org/10.1038/s41467-021-23327-1

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T1 - Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

AU - Kargapolova, Yulia

AU - Rehimi, Rizwan

AU - Kayserili, Hülya

AU - Brühl, Joanna

AU - Sofiadis, Konstantinos

AU - Zirkel, Anne

AU - Palikyras, Spiros

AU - Mizi, Athanasia

AU - Li, Yun

AU - Yigit, Gökhan

AU - Hoischen, Alexander

AU - Frank, Stefan

AU - Russ, Nicole

AU - Trautwein, Jonathan

AU - van Bon, Bregje

AU - Gilissen, Christian

AU - Laugsch, Magdalena

AU - Gusmao, Eduardo Gade

AU - Josipovic, Natasa

AU - Altmüller, Janine

AU - Nürnberg, Peter

AU - Längst, Gernot

AU - Kaiser, Frank J.

AU - Watrin, Erwan

AU - Brunner, Han

AU - Rada-Iglesias, Alvaro

AU - Kurian, Leo

AU - Wollnik, Bernd

AU - Bouazoune, Karim

AU - Papantonis, Argyris

PY - 2021/5/21

Y1 - 2021/5/21

N2 - Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.

AB - Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.

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Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

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