Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease.
Nearly all human genetic disorders result from a limited repertoire of mutations in an associated gene or its regulatory elements. We recently described an individual with an inherited form of anemia (alpha-thalassemia) who has a deletion that results in a truncated, widely expressed gene (LUC7L) becoming juxtaposed to a structurally normal alpha-globin gene (HBA2). Although it retains all of its local and remote cis-regulatory elements, expression of HBA2 is silenced and its CpG island becomes completely methylated early during development. Here we show that in the affected individual, in a transgenic model and in differentiating embryonic stem cells, transcription of antisense RNA mediates silencing and methylation of the associated CpG island. These findings identify a new mechanism underlying human genetic disease.
Tufarelli
Cristina
C
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Stanley
Jackie A Sloane
JA
Garrick
David
D
Sharpe
Jackie A
JA
Ayyub
Helena
H
Wood
William G
WG
Higgs
Douglas R
DR
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D018899:CpG Islands; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D020868:Gene Silencing; D005914:Globins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D016372:RNA, Antisense / Q000235:genetics*; D014158:Transcription, Genetic; D017085:alpha-Thalassemia / Q000235:genetics*
D016372:RNA, Antisense; D005914:Globins; D004247:DNA