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

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.

• Authors: 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
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 100 Issue 6 Pg. 907-925 (Jun 01 2017) ISSN: 1537-6605 [Electronic] United States
• PMID: 28575647 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• Histones
• YY1 Transcription Factor

Topics

• Acetylation
• Adolescent
• Base Sequence
• Child, Preschool
• Chromatin (metabolism)
• Chromatin Immunoprecipitation
• Cohort Studies
• Enhancer Elements, Genetic (genetics)
• Female
• Gene Ontology
• Haploinsufficiency (genetics)
• Haplotypes (genetics)
• Hemizygote
• Histones (metabolism)
• Humans
• Intellectual Disability (genetics)
• Lymphocytes (metabolism)
• Male
• Methylation
• Models, Molecular
• Mutation, Missense (genetics)
• Protein Binding (genetics)
• Protein Domains
• Transcription, Genetic
• YY1 Transcription Factor (chemistry, genetics)