Asset Details
Do you wish to reserve the book?
Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome
Do you wish to request the book?
Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome
2017
Overview
A pharmacological screen has identified the histone methyltransferase G9a as a target to reactivate imprinted genes in a mouse model of Prader–Willi Syndrome that improves growth and survival.
Prader–Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11–q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642—two selective inhibitors of euchromatic histone lysine
N
-methyltransferase-2 (EHMT2, also known as G9a)—activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster
SNORD116
, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (
Snrpn
(
S
)) to ubiquitin protein ligase E3A (
Ube3a
(
U
)) (mouse model referred to hereafter as
m
+
/p
ΔS−U
). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of
m
+
/p
ΔS−U
newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ DNA
/ Enzyme Inhibitors - pharmacology
/ Enzymes
/ Female
/ Gene Expression - drug effects
/ Histone-Lysine N-Methyltransferase - antagonists & inhibitors
/ Humans
/ Male
/ Mice
/ Prader-Willi Syndrome - genetics
/ Prader-Willi Syndrome - metabolism
/ Reverse Transcriptase Polymerase Chain Reaction
/ RNA, Small Nucleolar - drug effects
/ RNA, Small Nucleolar - genetics
/ Rodents
