Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brain.

Julio D Perez,Stephen W Santoro,Mariela Zirlinger,Catherine Dulac,Olivia Ho-Shing,Shau-Kwaun Chen,Nimrod D Rubinstein,John J Choi,Daniel E Fernandez,Leigh A Needleman,Jun S Liu

doi:10.7554/elife.07860

Abstract

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.

Highlights

In mammalian brains, neural computations underlying signal processing and behavioral control are conducted by a large diversity of cell types, each defined by unique but flexible patterns of connectivity, electrical properties, and profiles of gene expression and chromatin states (Fishell and Heintz, 2013)
Half of the cerebella were collected at postnatal day 8 (P8), a period in which newly-born granule cells migrate to the inner granule layer
Functional insights into the role of genomic imprinting in the apoptotic pathway In order to gain initial insights into the functional implications of the observed patterns of parental bias across the brain, we investigated whether specific biological pathways are enriched among cerebellum-imprinted genes

Summary

Introduction

Neural computations underlying signal processing and behavioral control are conducted by a large diversity of cell types, each defined by unique but flexible patterns of connectivity, electrical properties, and profiles of gene expression and chromatin states (Fishell and Heintz, 2013). Genomic imprinting is a unique and long lasting form of epigenetic inheritance that relies on chromatin modifications or ‘imprints’ established in the parental germ lines and maintained in cells of the developing and adult organism, resulting in the differential expression of the maternally- or the paternally-inherited allele (Bartolomei and Ferguson-Smith, 2011). Imprinted genes have been shown to play key roles during embryonic development (Cleaton et al, 2014), in the placenta (Tunster et al, 2013), and more recently, in the developing and adult brain (Wilkinson et al, 2007; Keverne, 2012)

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