RESUMEN
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.
Asunto(s)
Cromatina/metabolismo , Haploinsuficiencia/genética , Discapacidad Intelectual/genética , Transcripción Genética , Factor de Transcripción YY1/genética , Acetilación , Adolescente , Secuencia de Bases , Preescolar , Inmunoprecipitación de Cromatina , Estudios de Cohortes , Elementos de Facilitación Genéticos/genética , Femenino , Ontología de Genes , Haplotipos/genética , Hemicigoto , Histonas/metabolismo , Humanos , Linfocitos/metabolismo , Masculino , Metilación , Modelos Moleculares , Mutación Missense/genética , Unión Proteica/genética , Dominios Proteicos , Factor de Transcripción YY1/químicaRESUMEN
The discovery of mutations causing human disease has so far been biased toward protein-coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel resequencing of the nonrepetitive genomic linkage interval at Xq28 of family MRX3. We identified in the binding site of transcription factor YY1 a regulatory mutation that leads to overexpression of the chromatin-associated transcriptional regulator HCFC1. When tested on embryonic murine neural stem cells and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and a considerable reduction in neurite growth. Two other nonsynonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function.