Epigenetics in Prader-Willi Syndrome

Abstract

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that affects approximately 1 in 20,000 individuals worldwide. Symptom progression in PWS is classically characterized by two nutritional stages. Stage 1 is hypotonia characterized by poor muscle tone that leads to poor feeding behavior causing failure to thrive in early neonatal life. Stage 2 is followed by the development of extreme hyperphagia, also known as insatiable eating and fixation on food that often leads to obesity in early childhood. Other major features of PWS include obsessive-compulsive and hoarding behaviors, intellectual disability, and sleep abnormalities. PWS is genetic disorder mapping to imprinted 15q11.2-q13.3 locus, specifically at the paternally expressed SNORD116 locus of small nucleolar RNAs and noncoding host gene transcripts. SNORD116 is processed into several noncoding components and is hypothesized to orchestrate diurnal changes in metabolism through epigenetics, according to functional studies. Here, we review the current status of epigenetic mechanisms in PWS, with an emphasis on an emerging role for SNORD116 in circadian and sleep phenotypes. We also summarize current ongoing therapeutic strategies, as well as potential implications for more common human metabolic and psychiatric disorders.

Proteins and proteases of Prader–Willi syndrome: a comprehensive review and perspectives

“…This mechanism establishes the original silencing of maternal chromosome. Recently, the existence of separate somatic imprints in this silencing activity has been uncovered [70,71]. The epigenetic DNA-methylation that is mediated by DNA methyltransferase enzyme has been considered as a therapeutic target for possible management of PWS.…”

“…The first proof of principle of this approach was obtained when it was shown that a DNA methyltransferase inhibitor, '5-azadeoxycytidine' was able to demethylate the PWS-IC leading to activation of the maternal genes. Therefore, activation of the normally silent such maternal gene inhibitory compound may offer a potential therapeutic intervention and treatment for PWS patients [70,71]. Recently, a protein named 'ZNF-274' (Zinc Finger Protein 274) that contains five Zinc-finger domains has been identified [72], which plays important role in the suppression of maternal chromosome-15q11-q13 allele.…”

The Role of Long Non-coding RNAs in Human Imprinting Disorders: Prospective Therapeutic Targets

“…On the paternal allele of imprinted human PWS/AS locus, the unmethylated PWS-ICR is the region upstream to a protein-coding gene SNRPN and a lncRNA SNHG14 (small nucleolar RNA host gene 14) ( Sutcliffe et al, 1994 ; Buiting et al, 1995 ; Rougeulle et al, 1997 ; Runte et al, 2001 ; Vitali et al, 2010 ; Chamberlain, 2013 ; Stanurova et al, 2018 ; Figure 4A ). The neuron-specific non-coding transcript SNHG14 is processed to give rise to a series of non-coding RNA products, such as repeated C/D box small nucleolar RNAs (snoRNAs) and lncRNAs including 116HG , 115HG , and the antisense transcript to UBE3A ( Mendiola and LaSalle, 2021 ; Figure 4A ). The most studied RNA product from the host transcript SNHG14 is SNORD116 snoRNA, embedded within intronic regions of SNORD116 gene locus ( Cavaillé et al, 2000 ; de los Santos et al, 2000 ; Stanurova et al, 2018 ; Mendiola and LaSalle, 2021 ).…”

“…The neuron-specific non-coding transcript SNHG14 is processed to give rise to a series of non-coding RNA products, such as repeated C/D box small nucleolar RNAs (snoRNAs) and lncRNAs including 116HG , 115HG , and the antisense transcript to UBE3A ( Mendiola and LaSalle, 2021 ; Figure 4A ). The most studied RNA product from the host transcript SNHG14 is SNORD116 snoRNA, embedded within intronic regions of SNORD116 gene locus ( Cavaillé et al, 2000 ; de los Santos et al, 2000 ; Stanurova et al, 2018 ; Mendiola and LaSalle, 2021 ). SNORD116 snoRNA present in ribonucleoprotein complexes (snoRNPs) and may participate in splicing, ribosomal RNA maturation, RNA modifications, and regulation of prohormone processing-related gene expression ( Bazeley et al, 2008 ; Burnett et al, 2017 ).…”

“…The overlap between the phenotype caused by SNORD116 microdeletion and MAGEL2 mutation suggests that transcripts from SNORD116 locus may modify MAGEL2 expression via long-range chromatin interactions ( Meziane et al, 2015 ; Fountain and Schaaf, 2016 ; Langouët et al, 2018 ). The loss of the paternal expressed SNORD116 in PWS can be caused by several factors, including large paternal deletions in the imprinted PWS/AS locus (60%), maternal UPD (36%), small microdeletion in SNORD116 locus (<1%), and epigenetic alternations in DNA methylation of the PWS-ICR region (4%) ( Sahoo et al, 2008 ; Duker et al, 2010 ; Bieth et al, 2015 ; Rozhdestvensky et al, 2016 ; Mendiola and LaSalle, 2021 ; Figure 4B ). Rare microdeletions that encompass SNORD116 and its adjacent genes, SNRPN or SNORD115 , have been found in PWS patients ( Sahoo et al, 2008 ; de Smith et al, 2009 ; Duker et al, 2010 ).…”