Molecular underpinnings of Prader-Willi syndrome

ABSTRACT
Prader-Willi syndrome (PWS) is a neurogenetic disorder caused by the loss of paternally
inherited genes on chromosome 15q11-q13. Atypical deletions that cause PWS have narrowed
the genetic region critical for the disorder to a 91kb locus including SNORD116. SNORD116 is
cluster of 30 highly similar C/D box small nucleolar RNAs (snoRNAs). Canonical C/D box
snoRNAs anneal to and mediate 2'O-methylation (2'-OMe) of ribosomal RNAs, however, the
SNORD116 copies lack complementarity to rRNAs. Instead they are hypothesized to modify
mRNAs or lncRNAs, but direct targets for SNORD116 have not been identified. Thus, their
function in neurons is not known. Fortunately, every individual with PWS has an intact, but
epigenetically repressed copy of the PWS critical region, including SNORD116, on their
maternal allele. We have recently shown that the maternal copy of SNORD116 can be activated
in PWS neurons by depleting ZNF274, a KRAB domain zinc finger protein. Not only does this
suggest an intriguing therapeutic approach to PWS, but also provides a critical tool to help
understand how SNORD116 is regulated in neurons. The overall goal of this proposal is to
better understand the molecular underpinnings of PWS. We will determine the chromatin states
and long-range chromatin interactions of active and inactive 15q11-q13 alleles in iPSCs and
neuronal derivatives. We will investigate how activation of SNORD116 via ZNF274 depletion
and histone methyltransferase inhibition impact the chromatin state and long-range interactions.
Finally, we will identify the direct 2'-O-methylation targets of SNORD116 and determine how
they influence PWS-related differentially expressed genes.

Grant Number: 5R01HD099975-05
NIH Institute/Center: NIH
Principal Investigator: Gordon Carmichael