In silico comparative genomic analysis of GABAA receptor transcriptional regulation

Subtypes of the GABAA receptor subunit exhibit diverse temporal and spatial expression patterns. In silico comparative analysis was used to predict transcriptional regulatory features in individual mammalian GABAA receptor subunit genes, and to identify potential transcriptional regulatory components involved in the coordinate regulation of the GABAA receptor gene clusters.

Previously unreported putative promoters were identified for the beta2, gamma1, gamma3, epsilon, theta and pi subunit genes. Putative core elements and proximal transcriptional factors were identified within these predicted promoters, and within the experimentally determined promoters of other subunit genes. Conserved intergenic regions of sequence in the mammalian GABAA receptor gene cluster comprising the alpha1, beta2, gamma2 and alpha6 subunits were identified as potential long range transcriptional regulatory components involved in the coordinate regulation of these genes. A region of predicted DNase I hypersensitive sites within the cluster may contain transcriptional regulatory features coordinating gene expression. A novel model is proposed for the coordinate control of the gene cluster and parallel expression of the alpha1 and beta2 subunits, based upon the selective action of putative Scaffold/Matrix Attachment Regions (S/MARs).

The putative regulatory features identified by genomic analysis of GABAA receptor genes were substantiated by cross-species comparative analysis and now require experimental verification. The proposed model for the coordinate regulation of genes in the cluster accounts for the head-to-head orientation and parallel expression of the alpha1 and beta2 subunit genes, and for the disruption of transcription caused by insertion of a neomycin gene in the close vicinity of the alpha6 gene, which is proximal to a putative critical S/MAR.