Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons

Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger pro...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Langouet, Maeva, Gorka, Dea, Orniacki, Clarisse, Dupont-Thibert, Clemence M, Chung, Michael S, Glatt-Deeley, Heather R, Germain, Noelle, Crandall, Leann J, Cotney, Justin L, Stoddard, Christopher E, Lalande, Marc, Chamberlain, Stormy J
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.06.2020
Subjects
Alleles
Binding sites
Chromosome 15
CRISPR
Gene expression
Genomes
Hyperphagia
Inhibitory postsynaptic potentials
Neonates
Neurons
Prader-Willi syndrome
Zinc finger proteins
Online AccessGet full text

Cover

More Information
Summary:Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS iPSCs. However, ZNF274 has many other targets in the genome in addition to SNORD116. Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared to ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116. These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.06.13.149864