DNA Methylation Regulates Transcription Factor-Specific Neurodevelopmental but Not Sexually Dimorphic Gene Expression Dynamics in Zebra Finch Telencephalon.

Jolien Diddens,Louis Coussement,Charlotte A Cornil,Gaurav Majumdar,Tim De Meyer,Jeroen Galle,Annemie Van Der Linden,Wim Van Criekinge,Jacques Balthazart,Wim Vanden Berghe,Carolina Frankl-Vilches,Sita M Ter Haar,Sandra Steyaert,Ellen De Meester,Sarah De Keulenaer

doi:10.3389/fcell.2021.583555

Abstract

Song learning in zebra finches (Taeniopygia guttata) is a prototypical example of a complex learned behavior, yet knowledge of the underlying molecular processes is limited. Therefore, we characterized transcriptomic (RNA-sequencing) and epigenomic (RRBS, reduced representation bisulfite sequencing; immunofluorescence) dynamics in matched zebra finch telencephalon samples of both sexes from 1 day post hatching (1 dph) to adulthood, spanning the critical period for song learning (20 and 65 dph). We identified extensive transcriptional neurodevelopmental changes during postnatal telencephalon development. DNA methylation was very low, yet increased over time, particularly in song control nuclei. Only a small fraction of the massive differential expression in the developing zebra finch telencephalon could be explained by differential CpG and CpH DNA methylation. However, a strong association between DNA methylation and age-dependent gene expression was found for various transcription factors (i.e., OTX2, AR, and FOS) involved in neurodevelopment. Incomplete dosage compensation, independent of DNA methylation, was found to be largely responsible for sexually dimorphic gene expression, with dosage compensation increasing throughout life. In conclusion, our results indicate that DNA methylation regulates neurodevelopmental gene expression dynamics through steering transcription factor activity, but does not explain sexually dimorphic gene expression patterns in zebra finch telencephalon.

Highlights

Like humans, songbirds are one of the few animal groups that learn vocalizations (Jarvis, 2019)
P–value < 3.0E-25) and relevant effects observed for the expression of parvalbumin (10.4-fold increase with increasing age), GAD67 (GAD1) (3.3-fold increase), and OTX2 (27.3-fold decrease), which are crucially involved in the timing of critical periods (Bernard and Prochiantz, 2016)
Song learning in zebra finches is one of the most striking examples of a critical period for complex learned behavior (Kelly et al, 2018); this behavior as well as the underlying brain circuit is sexually dimorphic

Summary

Introduction

Songbirds are one of the few animal groups that learn vocalizations (Jarvis, 2019). Whereas female zebra finches (Taeniopygia guttata) lack the ability to sing, males learn their vocalizations from a tutor in early life, analogous to humans. They form an auditory memory template of the tutor song, to which they match their own vocalizations. This sexual dimorphism is reflected in the song control system, a series of interconnected telencephalic nuclei, which undergoes striking changes in morphology and connectivity during the song learning period. Given the many parallels with human (speech) learning, song birds are a commonly used model for neurobiological research (Drnevich et al, 2012; Brainard and Doupe, 2013)

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