Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.
Noncoding RNAs (ncRNA) participate in epigenetic regulation but are poorly understood. Here we characterize the transcriptional landscape of the four human HOX loci at five base pair resolution in 11 anatomic sites and identify 231 HOX ncRNAs that extend known transcribed regions by more than 30 kilobases. HOX ncRNAs are spatially expressed along developmental axes and possess unique sequence motifs, and their expression demarcates broad chromosomal domains of differential histone methylation and RNA polymerase accessibility. We identified a 2.2 kilobase ncRNA residing in the HOXC locus, termed HOTAIR, which represses transcription in trans across 40 kilobases of the HOXD locus. HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and is required for PRC2 occupancy and histone H3 lysine-27 trimethylation of HOXD locus. Thus, transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance; these results have broad implications for gene regulation in development and disease states.
Rinn
John L
JL
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Kertesz
Michael
M
Wang
Jordon K
JK
Squazzo
Sharon L
SL
Xu
Xiao
X
Brugmann
Samantha A
SA
Goodnough
L Henry
LH
Helms
Jill A
JA
Farnham
Peggy J
PJ
Segal
Eran
E
Chang
Howard Y
HY
D000818:Animals; D001483:Base Sequence / Q000235:genetics; D019521:Body Patterning / Q000235:genetics*; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D019175:DNA Methylation; D047108:Embryonic Development / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005801:Genes, Homeobox / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D063146:Polycomb-Group Proteins; D034622:RNA Interference / Q000502:physiology*; D022661:RNA, Untranslated / Q000737:chemistry / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics
D002843:Chromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D022661:RNA, Untranslated; D012097:Repressor Proteins