Abstract
Transcriptome analyses show a surprisingly large proportion of the mammalian genome is transcribed; much more than can be accounted for by genes and introns alone. Most of this transcription is non-coding in nature and arises from intergenic regions, often overlapping known protein-coding genes in sense or antisense orientation. The functional relevance of this widespread transcription is unknown. Here we characterize a promoter responsible for initiation of an intergenic transcript located approximately 3.3 kb and 10.7 kb upstream of the adult-specific human β-globin genes. Mutational analyses in β-YAC transgenic mice show that alteration of intergenic promoter activity results in ablation of H3K4 di- and tri-methylation and H3 hyperacetylation extending over a 30 kb region immediately downstream of the initiation site, containing the adult δ- and β-globin genes. This results in dramatically decreased expression of the adult genes through position effect variegation in which the vast majority of definitive erythroid cells harbor inactive adult globin genes. In contrast, expression of the neighboring ε- and γ-globin genes is completely normal in embryonic erythroid cells, indicating a developmentally specific variegation of the adult domain. Our results demonstrate a role for intergenic non-coding RNA transcription in the propagation of histone modifications over chromatin domains and epigenetic control of β-like globin gene transcription during development.
Highlights
A staggering proportion of the mammalian genome is transcribed
We show that alteration of intergenic promoter activity results in an adult stage-specific reduction in intergenic transcription and a domain-wide, markedly diminished histone modification profile compared to the normal active locus in transgenic mice, leading to dramatically reduced expression of the adult β-like globin genes
Absence of intergenic transcription results in altered histone modification profile We previously showed that YAC transgenes with a much larger (2.5 kb) δβ promoter deletion resulted in a 2- to 3-fold reduction in general DNase I sensitivity over the entire adult chromatin domain indicating that the normal, stage-specific chromatin opening of the domain surrounding the HBD and HBB genes failed in the absence of intergenic transcription [9]
Summary
A staggering proportion of the mammalian genome is transcribed. More than half of the transcribed genomic regions in mammalian cells are intergenic regions [1,2,3] producing vast amounts of non-coding RNAs [4]. Non-coding RNA and chromatin structure analysis, decision to publish, or preparation of the manuscript
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