YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction PMID: 28575647

RQC and Longevity Regulation

2026-09-03

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

Am J Hum Genet. 2017 Jun 1;100(6):907-925. doi: 10.1016/j.ajhg.2017.05.006.

Michele Gabriele ¹ , Anneke T Vulto-van Silfhout ² , Pierre-Luc Germain ¹ , Alessandro Vitriolo ¹ , Raman Kumar ³ , Evelyn Douglas ⁴ , Eric Haan ⁴ , Kenjiro Kosaki ⁵ , Toshiki Takenouchi ⁵ , Anita Rauch ⁶ , Katharina Steindl ⁶ , Eirik Frengen ⁷ , Doriana Misceo ⁷ , Christeen Ramane J Pedurupillay ⁷ , Petter Stromme ⁸ , Jill A Rosenfeld ⁹ , Yunru Shao ⁹ , William J Craigen ⁹ , Christian P Schaaf ⁹ , David Rodriguez-Buritica ¹⁰ , Laura Farach ¹⁰ , Jennifer Friedman ¹¹ , Perla Thulin ¹² , Scott D McLean ¹³ , Kimberly M Nugent ¹³ , Jenny Morton ¹⁴ , Jillian Nicholl ⁴ , Joris Andrieux ¹⁵ , Asbjørg Stray-Pedersen ¹⁶ , Pascal Chambon ¹⁷ , Sophie Patrier ¹⁸ , Sally A Lynch ¹⁹ , Susanne Kjaergaard ²⁰ , Pernille M Tørring ²¹ , Charlotte Brasch-Andersen ²¹ , Anne Ronan ²² , Arie van Haeringen ²³ , Peter J Anderson ²⁴ , Zöe Powis ²⁵ , Han G Brunner ² , Rolph Pfundt ² , Janneke H M Schuurs-Hoeijmakers ² , Bregje W M van Bon ² , Stefan Lelieveld ² , Christian Gilissen ² , Willy M Nillesen ² , Lisenka E L M Vissers ² , Jozef Gecz ²⁶ , David A Koolen ² , Giuseppe Testa ²⁷ , Bert B A de Vries ²⁸

Affiliations

1. Laboratory of Stem Cell Epigenetics, Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
2. Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
3. School of Medicine and Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
4. SA Clinical Genetics Service, SA Pathology, Adelaide, SA 5000, Australia; School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia.
5. Center for Medical Genetics, Keio University School of Medicine, 160-8582 Tokyo, Japan.
6. Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland.
7. Department of Medical Genetics, University of Oslo and Oslo University Hospital, 0315 Oslo, Norway.
8. Division of Paediatric and Adolescent Medicine, Oslo University Hospital and University of Oslo, 0313 Oslo, Norway.
9. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
10. Division of Genetics, Department of Pediatrics, University of Texas Health, Houston, TX 77030, USA.
11. Departments of Neurosciences and Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego, CA 92123, USA.
12. Department of Neurology, University of Utah, San Diego, CA 92123, USA.
13. Clinical Genetics Section, Children's Hospital of San Antonio, San Antonio, TX 78207, USA.
14. Birmingham Women's Hospital, B15 2TG Birmingham, UK.
15. Institut de Génétique Médicale, Hopital Jeanne de Flandre, 59000 Lille, France.
16. Human and Medical Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
17. Laboratory of Cytogenetics, Rouen University Hospital, 76031 Rouen, France.
18. Service d'Anatomie Pathologique, Rouen University Hospital, 76031 Rouen, France.
19. National Centre for Medical Genetics, Our Lady's Children's Hospital, D12 V004 Dublin, Ireland.
20. Department of Clinical Genetics, Rigshospitalet, 2100 Copenhagen, Denmark.
21. Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
22. Hunter Genetics, Waratah, NSW 2298, Australia.
23. Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
24. Australian Craniofacial Unit, Women's and Children's Hospital, North Adelaide, SA 5006, Australia.
25. Ambry Genetics, Aliso Viejo, CA 92656, USA.
26. School of Medicine and Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
27. Laboratory of Stem Cell Epigenetics, Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy. Electronic address: [email protected].
28. Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: [email protected].

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.