Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF.
Prior studies of the DM1 locus have shown that the CTG repeats are a component of a CTCF-dependent insulator element and that repeat expansion results in conversion of the region to heterochromatin. We now show that the DM1 insulator is maintained in a local heterochromatin context: an antisense transcript emanating from the adjacent SIX5 regulatory region extends into the insulator element and is converted into 21 nucleotide (nt) fragments with associated regional histone H3 lysine 9 (H3-K9) methylation and HP1gamma recruitment that is embedded within a region of euchromatin-associated H3 lysine 4 (H3-K4) methylation. CTCF restricts the extent of the antisense RNA at the wild-type (wt) DM1 locus and constrains the H3-K9 methylation to the nucleosome associated with the CTG repeat, whereas the expanded allele in congenital DM1 is associated with loss of CTCF binding, spread of heterochromatin, and regional CpG methylation.
Cho
Diane H
DH
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Thienes
Cortlandt P
CP
Mahoney
Sarah E
SE
Analau
Erwin
E
Filippova
Galina N
GN
Tapscott
Stephen J
SJ
D000076246:CCCTC-Binding Factor; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D038101:Insulator Elements / Q000235:genetics; D008745:Methylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D040641:Quantitative Trait Loci / Q000235:genetics*; D016372:RNA, Antisense / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics*
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D006657:Histones; D018398:Homeodomain Proteins; D016372:RNA, Antisense; D012097:Repressor Proteins; C106687:SIX5 protein, human