Dataset Information

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.

SUBMITTER: Gabriele M

PROVIDER: S-EPMC5473733 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Gabriele Michele M Vulto-van Silfhout Anneke T AT Germain Pierre-Luc PL Vitriolo Alessandro A Kumar Raman R Douglas Evelyn E Haan Eric E Kosaki Kenjiro K Takenouchi Toshiki T Rauch Anita A Steindl Katharina K Frengen Eirik E Misceo Doriana D Pedurupillay Christeen Ramane J CRJ Stromme Petter P Rosenfeld Jill A JA Shao Yunru Y Craigen William J WJ Schaaf Christian P CP Rodriguez-Buritica David D Farach Laura L Friedman Jennifer J Thulin Perla P McLean Scott D SD Nugent Kimberly M KM Morton Jenny J Nicholl Jillian J Andrieux Joris J Stray-Pedersen Asbjørg A Chambon Pascal P Patrier Sophie S Lynch Sally A SA Kjaergaard Susanne S Tørring Pernille M PM Brasch-Andersen Charlotte C Ronan Anne A van Haeringen Arie A Anderson Peter J PJ Powis Zöe Z Brunner Han G HG Pfundt Rolph R Schuurs-Hoeijmakers Janneke H M JHM van Bon Bregje W M BWM Lelieveld Stefan S Gilissen Christian C Nillesen Willy M WM Vissers Lisenka E L M LELM Gecz Jozef J Koolen David A DA Testa Giuseppe G de Vries Bert B A BBA

American journal of human genetics 20170601 6

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 d ...[more]

PMID: 28575647

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Project description:Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ~230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.

Dataset Information

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

Publications

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

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