Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/106217
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Type: Journal article
Title: YY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunction
Author: Gabriele, M.
Vulto-van Silfhout, A.
Germain, P.
Vitriolo, A.
Kumar, R.
Douglas, E.
Haan, E.
Kosaki, K.
Takenouchi, T.
Rauch, A.
Steindl, K.
Frengen, E.
Misceo, D.
Pedurupillay, C.
Stromme, P.
Rosenfeld, J.
Shao, Y.
Craigen, W.
Schaaf, C.
Rodriguez-Buritica, D.
et al.
Citation: American Journal of Human Genetics, 2017; 100(6):907-925
Publisher: Cell Press
Issue Date: 2017
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
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-Buritica, Laura 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
Abstract: 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.
Keywords: H3K27Ac; YY1; chromatin; enhancer; epigenetics; haploinsufficiency; intellectual disability; neurodevelopment; syndrome; transcription factor
Rights: © 2017 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
RMID: 0030070914
DOI: 10.1016/j.ajhg.2017.05.006
Appears in Collections:Genetics publications

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