Genetic and epigenetic characteristics of FSHD-associated 4q and 10q D4Z4 that are distinct from non-4q/10q D4Z4 homologs.
Facioscapulohumeral dystrophy (FSHD) is one of the most prevalent muscular dystrophies. The majority of FSHD cases are linked to a decreased copy number of D4Z4 macrosatellite repeats on chromosome 4q (FSHD1). Less than 5% of FSHD cases have no repeat contraction (FSHD2), most of which are associated with mutations of SMCHD1. FSHD is associated with the transcriptional derepression of DUX4 encoded within the D4Z4 repeat, and SMCHD1 contributes to its regulation. We previously found that the loss of heterochromatin mark (i.e., histone H3 lysine 9 tri-methylation (H3K9me3)) at D4Z4 is a hallmark of both FSHD1 and FSHD2. However, whether this loss contributes to DUX4 expression was unknown. Furthermore, additional D4Z4 homologs exist on multiple chromosomes, but they are largely uncharacterized and their relationship to 4q/10q D4Z4 was undetermined. We found that the suppression of H3K9me3 results in displacement of SMCHD1 at D4Z4 and increases DUX4 expression in myoblasts. The DUX4 open reading frame (ORF) is disrupted in D4Z4 homologs and their heterochromatin is unchanged in FSHD. The results indicate the significance of D4Z4 heterochromatin in DUX4 gene regulation and reveal the genetic and epigenetic distinction between 4q/10q D4Z4 and the non-4q/10q homologs, highlighting the special role of the 4q/10q D4Z4 chromatin and the DUX4 ORF in FSHD.
Department of Biological Chemistry, School of Medicine, University of California, Irvine, California; Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, California.
Weihua
W
Zeng
Yen-Yun
YY
Chen
Daniel A
DA
Newkirk
Beibei
B
Wu
Judit
J
Balog
Xiangduo
X
Kong
Alexander R
AR
Ball
Simona
S
Zanotti
Rabi
R
Tawil
Naohiro
N
Hashimoto
Ali
A
Mortazavi
Silvère M
SM
van der Maarel
Kyoko
K
Yokomori
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D002879:Chromosomes, Human, Pair 10; D002894:Chromosomes, Human, Pair 4; D006224:Cricetinae; D004276:DNA, Satellite; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D016366:Open Reading Frames; D061251:Primary Cell Culture; D012689:Sequence Homology, Nucleic Acid
D002868:Chromosomal Proteins, Non-Histone; D004276:DNA, Satellite; C121257:DUX4L1 protein, human; D006570:Heterochromatin; D006657:Histones; D018398:Homeodomain Proteins; C578241:SMCHD1 protein, human
D4Z4; DUX4; FSHD1; FSHD2; H3K9me3; SMCHD1; heterochromatin