FoxP2 isoforms delineate spatiotemporal transcriptional networks for vocal learning in the zebra finch
- University of California, Los Angeles, United States
- Stanford University, United States
Abstract
Human speech is one of the few examples of vocal learning among mammals yet ~half of avian species exhibit this ability. Its neurogenetic basis is largely unknown beyond a shared requirement for FoxP2 in both humans and zebra finches. We manipulated FoxP2 isoforms in Area X, a song-specific region of the avian striatopallidum analogous to human anterior striatum, during a critical period for song development. We delineate, for the first time, unique contributions of each isoform to vocal learning. Weighted gene coexpression network analysis of RNA-seq data revealed gene modules correlated to singing, learning, or vocal variability. Coexpression related to singing was found in juvenile and adult Area X whereas coexpression correlated to learning was unique to juveniles. The confluence of learning and singing coexpression in juvenile Area X may underscore molecular processes that drive vocal learning in young zebra finches and, by analogy, humans.
Data availability
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Weighted gene coexpression analysis of RNA-seq data from 65d juvenile Area X and adjacent non-song ventral striatopallidum (VSP).Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE96843).
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Weighted gene co-expression network analysis on microarray data from subregions of zebra finch (Taeniopygia guttata) basal gangliaPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE34819).
Article and author information
Author details
Zachary Daniel Burkett
Funding
National Institutes of Health (RO1MH07012)
- Stephanie A White
National Institutes of Health (5T32HD007228)
- Zachary Daniel Burkett
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal use was in accordance with NIH guidelines for experiments involving vertebrate animals and approved by the University of California, Los Angeles Chancellor's Institutional Animal Care and Use Committee (IACUC) under protocol (#2001-54). All surgical procedures were performed under isoflurane anesthetic.
Copyright
© 2018, Burkett et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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FoxP2 isoforms delineate spatiotemporal transcriptional networks for vocal learning in the zebra finch
eLife 7:e30649.
https://doi.org/10.7554/eLife.30649
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Enhancers and promoters are classically considered to be bound by a small set of transcription factors (TFs) in a sequence-specific manner. This assumption has come under increasing skepticism as the datasets of ChIP-seq assays of TFs have expanded. In particular, high-occupancy target (HOT) loci attract hundreds of TFs with often no detectable correlation between ChIP-seq peaks and DNA-binding motif presence. Here, we used a set of 1003 TF ChIP-seq datasets (HepG2, K562, H1) to analyze the patterns of ChIP-seq peak co-occurrence in combination with functional genomics datasets. We identified 43,891 HOT loci forming at the promoter (53%) and enhancer (47%) regions. HOT promoters regulate housekeeping genes, whereas HOT enhancers are involved in tissue-specific process regulation. HOT loci form the foundation of human super-enhancers and evolve under strong negative selection, with some of these loci being located in ultraconserved regions. Sequence-based classification analysis of HOT loci suggested that their formation is driven by the sequence features, and the density of mapped ChIP-seq peaks across TF-bound loci correlates with sequence features and the expression level of flanking genes. Based on the affinities to bind to promoters and enhancers we detected five distinct clusters of TFs that form the core of the HOT loci. We report an abundance of HOT loci in the human genome and a commitment of 51% of all TF ChIP-seq binding events to HOT locus formation thus challenging the classical model of enhancer activity and propose a model of HOT locus formation based on the existence of large transcriptional condensates.
