Therapeutic Potential of Blocking Zinc Finger Protein 274 Binding to the PWS Locus

Our goal is to understand the molecular pathways disrupted in Prader-Willi syndrome (PWS) and to develop therapeutic interventions for this disorder. Through the biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that is switched on while the same set of genes on the chromosome 15 inherited from the mother is switched off. In PWS, there is no complete copy of the paternal chromosome 15 so PWS individuals only have the switched off copies that came from the mother’s chromosome 15. We have identified a component of the switch off mechanism, a protein called ZNF274, that binds only to the silent maternal chromosome 15 in stem cell lines created from PWS skin cells. We have depleted ZNF274 in these PWS stem cells, differentiated the ZNF274-depleted stem cells into neurons and succeeded in turning on the set of genes from the maternal chromosome 15. Unfortunately, completely depleting ZNF274 from cells can have unwanted consequences so, here, we are proposing to specifically interfere with ZNF274’s binding to the PWS locus. Our approach is to engineer a molecule called a CRISPR/de-activatedCas9 (dCas9) to specifically attach to the ZNF274 binding sites. To prepare for these experiments, we have determined the precise DNA nucleotide sequence of the binding site for ZNF274 so that we can target the dCas9 molecule to the ZNF274 binding sites and blocking the interaction between ZNF274 and the PWS locus, and activate the maternal PWS alleles.

This project was funded by the Foundation for Prader-Willi Research Canada

Research Outcomes:

Zinc finger protein 274 regulates imprinted expression of transcripts in Prader-Willi syndrome neurons. Langouët M, Glatt-Deeley HR, Chung MS, Dupont-Thibert CM, Mathieux E, Banda EC, Stoddard CE, Crandall L, Lalande M. Human Molecular Genetics. Feb 2018.

Funded Year:


Awarded to:

Marc Lalande, PhD




University of Connecticut Health Center


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