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.


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.

MeSH terms

  • 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
  • YY1 Transcription Factor / genetics*


  • Chromatin
  • Histones
  • YY1 Transcription Factor