Noncanonical Genomic Imprinting Effects in Offspring

Abstract

Here, we describe an RNA-sequencing (RNA-seq)-based approach that accurately detects even modest maternal or paternal allele expression biases at the tissue level, which we call noncanonical genomic imprinting effects. We profile imprinting in the arcuate nucleus (ARN) and dorsal raphe nucleus of the female mouse brain as well as skeletal muscle (mesodermal) and liver (endodermal). Our study uncovers hundreds of noncanonical autosomal and X-linked imprinting effects. Noncanonical imprinting is highly tissue-specific and enriched in the ARN, but rare in the liver. These effects are reproducible across different genetic backgrounds and associated with allele-specific chromatin. Using in situ hybridization for nascent RNAs, we discover that autosomal noncanonical imprinted genes with a tissue-level allele bias exhibit allele-specific expression effects in subpopulations of neurons in the brain in vivo. We define noncanonical imprinted genes that regulate monoamine signaling and determine that these effects influence the impact of inherited mutations on offspring behavior.

New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain

“…Genes may also exhibit various degrees of parental biases in different species. For instance, L3mbtl exhibits a paternal bias in the mouse hypothalamus (Bonthuis et al 2015), whereas its human ortholog is paternally expressed in most tissues (Babak et al 2015). Finally, in flowering plants, the only other organisms outside mammals exhibiting parent-of-origin imprinting, most imprinted genes display parental biases rather than monoallelic expression (Gehring 2013).…”

“…Highly sensitive expression measurements, such as RNA sequencing (RNA-seq), applied over many biological samples, analyzed with robust statistical methods, and independently validated, have led to accurate detection of a large spectrum of parental allelic biases (Bonthuis et al 2015, Crowley et al 2015, Perez et al 2015) (Figure 4a). In whole brain, specific adult and developing brain regions, and muscle (Bonthuis et al 2015, Crowley et al 2015, Perez et al 2015), the distribution of parental allelic expression ratios displays a clear bimodal shape, with one mode showing strong bias to monoallelic expression, whereas the other mode exhibits a weak bias (Figure 4b).…”

“…In whole brain, specific adult and developing brain regions, and muscle (Bonthuis et al 2015, Crowley et al 2015, Perez et al 2015), the distribution of parental allelic expression ratios displays a clear bimodal shape, with one mode showing strong bias to monoallelic expression, whereas the other mode exhibits a weak bias (Figure 4b). This pattern was observed neither in the liver, which expresses very few imprinted genes (Bonthuis et al 2015), nor in the placenta, where the latter is likely due to contamination from the maternal decidua (Finn et al 2014, Okae et al 2012). …”

“…Attempts in culture so far have highlighted significant variation in the allele-specific expression among single cells, making the results difficult to interpret (Herzing et al 2002, Jouvenot et al 1999). In mouse brain sections, Bonthuis et al (2015) reported monoallelic ISH nascent mRNA signals in a large fraction of cells for several parentally biased genes. However, because parental identity of the alleles was unavailable, monoallelic signals due to transcriptional bursts unsynchronized between the alleles cannot be ruled out.…”

“…In the brain monoaminergic system (Figure 6b), maternally biased genes generally increase monoamine levels, whereas paternally biased genes may selectively reduce their postsynaptic effects (Bonthuis et al 2015). Most notably, tyrosine hydroxylase (TH), which limits the rate of dopamine and norepinephrine synthesis, shows a weak maternal bias in monoaminergic nuclei.…”