Evolution of immune chemoreceptors into sensors of the outside world

Changes in gene expression patterns represent an essential source of evolutionary innovation. A striking case of neofunctionalization is the acquisition of neuronal specificity by immune formyl peptide receptors (Fprs). In mammals, Fprs are expressed by immune cells, where they detect pathogenic and inflammatory chemical cues. In rodents, these receptors are also expressed by sensory neurons of the vomeronasal organ, an olfactory structure mediating innate avoidance behaviors. Here we show that two gene shuffling events led to two independent acquisitions of neuronal specificity by Fprs. The first event targeted the promoter of a V1R receptor gene. This was followed some 30 million years later by a second genomic accident targeting the promoter of a V2R gene. Finally, we show that expression of a vomeronasal Fpr can reverse back to the immune system under inflammatory conditions via the production of an intergenic transcript linking neuronal and immune Fpr genes. Thus, three hijackings of regulatory elements are sufficient to explain all aspects of the complex expression patterns acquired by a receptor family that switched from sensing pathogens inside the organism to sensing the outside world through the nose.

A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster

We have identified an intergenic transcriptional activity that is located between the human HOXA1 and HOXA2 genes, shows myeloid-specific expression, and is up-regulated during granulocytic differentiation. The novel gene, termed HOTAIRM1 (HOX antisense intergenic RNA myeloid 1), is transcribed antisense to the HOXA genes and originates from the same CpG island that embeds the start site of HOXA1. The transcript appears to be a noncoding RNA containing no long open-reading frame; sucrose gradient analysis shows no association with polyribosomal fractions. HOTAIRM1 is the most prominent intergenic transcript expressed and up-regulated during induced granulocytic differentiation of NB4 promyelocytic leukemia and normal human hematopoietic cells; its expression is specific to the myeloid lineage. Its induction during retinoic acid (RA)–driven granulocytic differentiation is through RA receptor and may depend on the expression of myeloid cell development factors targeted by RA signaling. Knockdown of HOTAIRM1 quantitatively blunted RA-induced expression of HOXA1 and HOXA4 during the myeloid differentiation of NB4 cells, and selectively attenuated induction of transcripts for the myeloid differentiation genes CD11b and CD18, but did not noticeably impact the more distal HOXA genes. These findings suggest that HOTAIRM1 plays a role in the myelopoiesis through modulation of gene expression in the HOXA cluster.

Dicer-Dependent Turnover of Intergenic Transcripts from the Human β-Globin Gene Cluster

ABSTRACT The widespread occurrence of intergenic transcription in eukaryotes is increasingly evident. Intergenic transcription in the β-globin gene cluster has been described in murine and human cells, and models for a role in gene and chromatin activation have been proposed. In this study, we analyze intergenic transcription and the chromatin state throughout the human β-globin gene cluster and find that the data are not consistent with such activation-linked models. Thus, intergenic transcript levels correlate with neither chromatin activation nor globin gene expression. Instead, we find that intergenic transcripts of the β-globin gene cluster are specifically upregulated in Dicer-deficient cells. This is accompanied by a shift towards more activated chromatin as indicated by changes in histone tail modifications. Our results strongly implicate RNA interference (RNAi)-related mechanisms in regulating intergenic transcription in the human β-globin gene cluster and further suggest that RNAi-dependent chromatin silencing in vertebrates is not restricted to the centromeres.