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Functionality of intergenic transcription: an evolutionary comparison.

ABSTRACT: Although a large proportion of human transcription occurs outside the boundaries of known genes, the functional significance of this transcription remains unknown. We have compared the expression patterns of known genes as well as intergenic transcripts within the ENCODE regions between humans and chimpanzees in brain, heart, testis, and lymphoblastoid cell lines. We find that intergenic transcripts show patterns of tissue-specific conservation of their expression, which are comparable to exonic transcripts of known genes. This suggests that intergenic transcripts are subject to functional constraints that restrict their rate of evolutionary change as well as putative positive selection to an extent comparable to that of classical protein-coding genes. In brain and testis, we find that part of this intergenic transcription is caused by widespread use of alternative promoters. Further, we find that about half of the expression differences between humans and chimpanzees are due to intergenic transcripts.

SUBMITTER: Khaitovich P

PROVIDER: S-EPMC1599769 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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Functionality of intergenic transcription: an evolutionary comparison.

Khaitovich Philipp P Kelso Janet J Franz Henriette H Visagie Johann J Giger Thomas T Joerchel Sabrina S Petzold Ekkehard E Green Richard E RE Lachmann Michael M Pääbo Svante S

PLoS genetics 20060828 10

Although a large proportion of human transcription occurs outside the boundaries of known genes, the functional significance of this transcription remains unknown. We have compared the expression patterns of known genes as well as intergenic transcripts within the ENCODE regions between humans and chimpanzees in brain, heart, testis, and lymphoblastoid cell lines. We find that intergenic transcripts show patterns of tissue-specific conservation of their expression, which are comparable to exonic ...[more]

PMID: 17040132

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Project description:Although a large proportion of human transcription occurs outside the boundaries of known genes, the functional significance of this transcription remains unknown. We have compared the expression patterns of known genes as well as intergenic transcripts within the ENCODE regions between humans and chimpanzees in brain, heart, testis and lymphoblastoid cell lines. We find that intergenic transcripts show patterns of tissue-specific conservation of their expression which are comparable to exonic transcripts of known genes. This suggests that intergenic transcripts are subject to functional constraints that restrict their rate of evolutionary change as well as putative positive selection to an extent comparable to that of classical protein-coding genes. In brain and testis, we find that part of this intergenic transcription is caused by wide-spread use of alternative promoters. Further, we find that about half of the expression differences between humans and chimpanzees are due to intergenic transcripts. In order to transfer genetic information encoded in the genomic sequence of an organism into functional features, the genomic sequence must be transcribed. According to the current genome annotation, the human genome produces transcripts from 20,00025,000 protein-coding genes and a smaller number of non-coding genes. Recently, the introduction of tiling arrays that enable the measurement of transcription regardless of previous annotation challenged this view by providing evidence that a large proportion of transcription occurs outside of annotated genes. It has been suggested that these transcripts represent previously unidentified functional RNAs as well as extensions of known genes. However, their lack of conservation between species on the DNA sequence level raises questions about their functionality. In this study we assess the functionality of these novel transcripts by testing the extent to which their expression is conserved between humans and chimpanzees in different tissues. Surprisingly, we find the expression of known and novel transcripts to be conserved to the same relative extent when different tissues are compared. This suggests that both known and novel transcripts are equally affected by adaptive and stabilizing selection in different tissues during human and chimpanzee evolution. Further, in terms of absolute numbers, about half of the expression differences between humans and chimpanzees in any given tissue are due to intergenic transcripts.

Project description:BackgroundIn the mammalian genome, a substantial number of gene pairs (approximately 10%) are arranged head-to-head on opposite strands within 1,000 base pairs, and separated by a bidirectional promoter(s) that generally drives the co-expression of both genes and results in functional coupling. The significance of unique genomic configuration remains elusive.Methodology/principal findingsHere we report on the identification of an intergenic region of non-homologous genes, CDT2, a regulator of DNA replication, and an integrator complex subunit 7 (INTS7), an interactor of the largest subunit of RNA polymerase II. The CDT2-INTS7 intergenic region is 246 and 245 base pairs long in human and mouse respectively and is evolutionary well-conserved among several mammalian species. By measuring the luciferase activity in A549 cells, the intergenic human sequence was shown to be able to drive the reporter gene expression in either direction and notably, among transcription factors E2F, E2F1 approximately E2F4, but not E2F5 and E2F6, this sequence clearly up-regulated the reporter gene expression exclusively in the direction of the CDT2 gene. In contrast, B-Myb, c-Myb, and p53 down-regulated the reporter gene expression in the transcriptional direction of the INTS7 gene. Overexpression of E2F1 by adenoviral-mediated gene transfer resulted in an increased CDT2, but not INTS7, mRNA level. Real-time polymerase transcription (RT-PCR) analyses of the expression pattern for CDT2 and INTS7 mRNA in human adult and fetal tissues and cell lines revealed that transcription of these two genes are asymmetrically regulated. Moreover, the abundance of mRNA between mouse and rat tissues was similar, but these patterns were quite different from the results obtained from human tissues.Conclusions/significanceThese findings add a unique example and help to understand the mechanistic insights into the regulation of gene expression through an evolutionary conserved intergenic region of the mammalian genome.

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Functionality of intergenic transcription: an evolutionary comparison.

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Functionality of intergenic transcription: an evolutionary comparison.

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