YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Michele Gabriele, Anneke T Vulto-van Silfhout, Pierre-Luc Germain, Alessandro Vitriolo, Raman Kumar, Evelyn Douglas, Eric Haan, Kenjiro Kosaki, Toshiki Takenouchi, Anita Rauch, Katharina Steindl, Eirik Frengen, Doriana Misceo, Christeen Ramane J Pedurupillay, Petter Stromme, Jill A Rosenfeld, Yunru Shao, William J Craigen, Christian P Schaaf, David Rodriguez-BuriticaLaura Farach, Jennifer Friedman, Perla Thulin, Scott D McLean, Kimberly M Nugent, Jenny Morton, Jillian Nicholl, Joris Andrieux, Asbjørg Stray-Pedersen, Pascal Chambon, Sophie Patrier, Sally A Lynch, Susanne Kjaergaard, Pernille M Tørring, Charlotte Brasch-Andersen, Anne Ronan, Arie van Haeringen, Peter J Anderson, Zöe Powis, Han G Brunner, Rolph Pfundt, Janneke H M Schuurs-Hoeijmakers, Bregje W M van Bon, Stefan Lelieveld, Christian Gilissen, Willy M Nillesen, Lisenka E L M Vissers, Jozef Gecz, David A Koolen, Giuseppe Testa, Bert B A de Vries

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Abstrakt

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind100
Udgave nummer6
Sider (fra-til)907-925
ISSN0002-9297
DOI
StatusUdgivet - 2017

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Citationsformater

Gabriele, M., Vulto-van Silfhout, A. T., Germain, P-L., Vitriolo, A., Kumar, R., Douglas, E., Haan, E., Kosaki, K., Takenouchi, T., Rauch, A., Steindl, K., Frengen, E., Misceo, D., Pedurupillay, C. R. J., Stromme, P., Rosenfeld, J. A., Shao, Y., Craigen, W. J., Schaaf, C. P., ... de Vries, B. B. A. (2017). YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction. American Journal of Human Genetics, 100(6), 907-925. https://doi.org/10.1016/j.ajhg.2017.05.006