Over-expression of the miRNA cluster at chromosome 14q32 in the alcoholic brain correlates with suppression of predicted target mRNA required for oligodendrocyte proliferation

We examined miRNA expression from RNA isolated from the frontal cortex (Broadman area 9) of 9 alcoholics (6 males, 3 females, mean age 48 years) and 9 matched controls using both the Affymetrix GeneChip miRNA 2.0 and Human Exon 1.0 ST Arrays to further characterize genetic influences in alcoholism and the effects of alcohol consumption on predicted target mRNA expression. A total of 12 human miRNAs were significantly up-regulated in alcohol dependent subjects (fold change ≥ 1.5, false discovery rate (FDR) ≤ 0.3; p < 0.05) compared with controls including a cluster of 4 miRNAs (e.g., miR-377, miR-379) from the maternally expressed 14q32 chromosome region. The status of the up-regulated miRNAs was supported using the high-throughput method of exon microarrays showing decreased predicted mRNA gene target expression as anticipated from the same RNA aliquot. Predicted mRNA targets were involved in cellular adhesion (e.g., THBS2), tissue differentiation (e.g., CHN2), neuronal migration (e.g., NDE1), myelination (e.g., UGT8, CNP) and oligodendrocyte proliferation (e.g., ENPP2, SEMA4D1). Our data support an association of alcoholism with up-regulation of a cluster of miRNAs located in the genomic imprinted domain on chromosome 14q32 with their predicted gene targets involved with oligodendrocyte growth, differentiation and signaling.     

Molecular evolution of the HBII-52 snoRNA cluster

HBII-52 is a human brain-specific C/D box snoRNA that potentially regulates the editing and/or alternative splicing of the serotonin receptor. Forty-two nearly identical copies of the HBII-52 gene are located immediately downstream of the SNRPN protein-coding gene in an imprinted locus associated with Prader-Willi syndrome. Other eutherian mammals, with genomic assemblies covering the corresponding locus, also have multiple orthologous copies of HBII-52. The SNRPB gene, which is known to have given rise to SNRPN through gene duplication, expresses a C/D box snoRNA, SNORD119, from its fifth intron. Here we show that, despite the fact that they lie in different positions relative to the orthologous SNRPB/SNRPN coding sequences, there are significant sequence similarities between SNORD119 and HBII-52, including the antisense element and the stem-forming regions. By analysing these snoRNAs in marsupial and eutherian mammal genomes, we reconstruct the likely evolutionary history of the HBII-52 cluster and SNORD119 and suggest that they have evolved from a common ancestor.