Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are oppositely imprinted 
autism-spectrum disorders with known genetic bases, but complex epigenetic 
mechanisms underlie their pathogenesis. The PWS/AS locus on 15q11-q13 is 
regulated by an imprinting control region that is maternally methylated and 
silenced. The PWS imprinting control region is the promoter for a one megabase 
paternal transcript encoding the ubiquitous protein-coding Snrpn gene and 
multiple neuron-specific noncoding RNAs, including the PWS-related Snord116 
repetitive locus of small nucleolar RNAs and host genes, and the antisense 
transcript to AS-causing ubiquitin ligase encoding Ube3a (Ube3a-ATS). 
Neuron-specific transcriptional progression through Ube3a-ATS correlates with 
paternal Ube3a silencing and chromatin decondensation. Interestingly, 
topoisomerase inhibitors, including topotecan, were recently identified in an 
unbiased drug screen for compounds that could reverse the silent paternal allele 
of Ube3a in neurons, but the mechanism of topotecan action on the PWS/AS locus 
is unknown. Here, we demonstrate that topotecan treatment stabilizes the 
formation of RNA:DNA hybrids (R loops) at G-skewed repeat elements within 
paternal Snord116, corresponding to increased chromatin decondensation and 
inhibition of Ube3a-ATS expression. Neural precursor cells from paternal 
Snord116 deletion mice exhibit increased Ube3a-ATS levels in differentiated 
neurons and show a reduced effect of topotecan compared with wild-type neurons. 
These results demonstrate that the AS candidate drug topotecan acts 
predominantly through stabilizing R loops and chromatin decondensation at the 
paternally expressed PWS Snord116 locus. Our study holds promise for targeted 
therapies to the Snord116 locus for both AS and PWS.