The maternal and paternal genomes play different roles in mammalian brains as a result of genomic imprinting, an epigenetic regulation leading to differential expression of the parental alleles of some genes. Here we investigate genomic imprinting in the cerebellum using a newly developed Bayesian statistical model that provides unprecedented transcript-level resolution. We uncover 160 imprinted transcripts, including 41 novel and independently validated imprinted genes. Strikingly, many genes exhibit parentally biased—rather than monoallelic—expression, with different magnitudes according to age, organ, and brain region. Developmental changes in parental bias and overall gene expression are strongly correlated, suggesting combined roles in regulating gene dosage. Finally, brain-specific deletion of the paternal, but not maternal, allele of the paternally-biased Bcl-x, (Bcl2l1) results in loss of specific neuron types, supporting the functional significance of parental biases. These findings reveal the remarkable complexity of genomic imprinting, with important implications for understanding the normal and diseased brain.
Most cells in the human body contain two copies of each chromosome—one that was inherited from the individual's mother and one from the father—and therefore contain two copies of every gene. While both copies are usually used equally and simultaneously to produce proteins, in a minority of cases the gene from one parent is silenced in a process known as genomic imprinting. This is generally achieved via the addition of chemical marks onto the DNA, which prevent the molecular machinery that activates genes from accessing the genetic material.
Previous efforts to map imprinting in the brain throughout the mouse genome have yielded inconsistent results, due in part to the large number of factors that can affect gene expression. Perez, Rubinstein, Fernandez et al. have now addressed this issue by applying a combined approach, which includes developing a powerful statistical model that takes into account variation in age, sex, and mouse strain and extensively validating each imprinted gene candidate using an independent experimental technique.
Perez, Rubinstein, Fernandez et al. analyzed genomic imprinting initially in a part of the brain called the cerebellum in both young and adult mice. This analysis confirmed the occurrence of imprinting in 74 genes identified in previous studies, and revealed imprinting for the first time in a further 41 genes. The degree of imprinting varied between genes. In some genes only one copy was expressed and the other was completely silenced whereas others only deviated from the two copies being expressed equally. For individual genes, imprinting varied with age, tending to be more pronounced in young animals than in adults. It also varied between brain regions and typically genes were imprinted more in the brain compared to elsewhere in the body.
Mapping the activities of the imprinted genes revealed that many are involved in regulating the process of controlled cell death, or ‘apoptosis’. For one particular test gene, selectively deleting either the maternal or paternal copy had different effects on the mice, thereby confirming that imprinting can affect brain development and activity. With this in mind, the potential impact of imprinting should also be considered when evaluating the effects of inherited mutations on human health.