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Title: Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

Abstract

DLX transcription factors (TFs) are master regulators of the developing vertebrate brain, driving forebrain GABAergic neuronal differentiation. Ablation of Dlx1&2 alters expression of genes that are critical for forebrain GABAergic development. We integrated epigenomic and transcriptomic analyses, complemented with in situ hybridization (ISH), and in vivo and in vitro studies of regulatory element (RE) function. This revealed the DLX-organized gene regulatory network at genomic, cellular, and spatial levels in mouse embryonic basal ganglia. DLX TFs perform dual activating and repressing functions; the consequences of their binding were determined by the sequence and genomic context of target loci. Our results reveal and, in part, explain the paradox of widespread DLX binding contrasted with a limited subset of target loci that are sensitive at the epigenomic and transcriptomic level to Dlx1&2 ablation. The regulatory properties identified here for DLX TFs suggest general mechanisms by which TFs orchestrate dynamic expression programs underlying neurodevelopment.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); NIMH; NIGMS
OSTI Identifier:
1557912
Alternate Identifier(s):
OSTI ID: 1623649; OSTI ID: 1650070
Grant/Contract Number:  
AC02-05CH11231; R37/R01 MH049428; R35 GM119831; R01HG003988
Resource Type:
Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Name: Cell Reports Journal Volume: 28 Journal Issue: 8; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Cell biology; DLX; transcription factor; enhancers; regulatory element; genome; transcriptional circuits; chromatin; histone; ChIP-seq; development; ganglionic eminence; GABA neuron; basal ganglia; telencephalon

Citation Formats

Lindtner, Susan, Catta-Preta, Rinaldo, Tian, Hua, Su-Feher, Linda, Price, James D., Dickel, Diane E., Greiner, Vanille, Silberberg, Shanni N., McKinsey, Gabriel L., McManus, Michael T., Pennacchio, Len A., Visel, Axel, Nord, Alex S., and Rubenstein, John L. R. Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons. Netherlands: N. p., 2019. Web. doi:10.1016/j.celrep.2019.07.022.
Lindtner, Susan, Catta-Preta, Rinaldo, Tian, Hua, Su-Feher, Linda, Price, James D., Dickel, Diane E., Greiner, Vanille, Silberberg, Shanni N., McKinsey, Gabriel L., McManus, Michael T., Pennacchio, Len A., Visel, Axel, Nord, Alex S., & Rubenstein, John L. R. Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons. Netherlands. https://doi.org/10.1016/j.celrep.2019.07.022
Lindtner, Susan, Catta-Preta, Rinaldo, Tian, Hua, Su-Feher, Linda, Price, James D., Dickel, Diane E., Greiner, Vanille, Silberberg, Shanni N., McKinsey, Gabriel L., McManus, Michael T., Pennacchio, Len A., Visel, Axel, Nord, Alex S., and Rubenstein, John L. R. Thu . "Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons". Netherlands. https://doi.org/10.1016/j.celrep.2019.07.022.
@article{osti_1557912,
title = {Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons},
author = {Lindtner, Susan and Catta-Preta, Rinaldo and Tian, Hua and Su-Feher, Linda and Price, James D. and Dickel, Diane E. and Greiner, Vanille and Silberberg, Shanni N. and McKinsey, Gabriel L. and McManus, Michael T. and Pennacchio, Len A. and Visel, Axel and Nord, Alex S. and Rubenstein, John L. R.},
abstractNote = {DLX transcription factors (TFs) are master regulators of the developing vertebrate brain, driving forebrain GABAergic neuronal differentiation. Ablation of Dlx1&2 alters expression of genes that are critical for forebrain GABAergic development. We integrated epigenomic and transcriptomic analyses, complemented with in situ hybridization (ISH), and in vivo and in vitro studies of regulatory element (RE) function. This revealed the DLX-organized gene regulatory network at genomic, cellular, and spatial levels in mouse embryonic basal ganglia. DLX TFs perform dual activating and repressing functions; the consequences of their binding were determined by the sequence and genomic context of target loci. Our results reveal and, in part, explain the paradox of widespread DLX binding contrasted with a limited subset of target loci that are sensitive at the epigenomic and transcriptomic level to Dlx1&2 ablation. The regulatory properties identified here for DLX TFs suggest general mechanisms by which TFs orchestrate dynamic expression programs underlying neurodevelopment.},
doi = {10.1016/j.celrep.2019.07.022},
journal = {Cell Reports},
number = 8,
volume = 28,
place = {Netherlands},
year = {Thu Aug 01 00:00:00 EDT 2019},
month = {Thu Aug 01 00:00:00 EDT 2019}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1016/j.celrep.2019.07.022

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Cited by: 41 works
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Figures / Tables:

Figure 1 Figure 1: DLX2, DLX1, and DLX5 Genomic Binding in Embryonic GE (A) Schematic of functional genomic dissection of DLX. (B) DLX ChIP-seq coverage at Gad2 and Lhx6 loci; merged peak dataset represented inside a golden box on top of first DLX track. (C) DLX peak counts by genomic feature atmore » E11.5, E13.5, and E16.5. (D) Heatmap showing pairwise Pearson correlation for genome-wide coverage values for DLX ChIP-seq. (E) Normalized coverage of ChIP-seq peaks. Each row represents a DLX binding region ± 10 kb. Numbers under the heatmap columns denote number of peaks called for each DLX/time point. (F) Venn diagrams showing increasing percent of peaks shared across DLXs as peak stringency increases. (G) Volcano plot showing E13.5 Dlx1/2−/− versus WT GE differential gene expression fold change and statistical significance. (H) Shared primary binding DNA motif across DLXs (i) centered within ChIP-seq peaks (ii). Motifs that were strongly enriched within DLX peaks (iii); blue bars show motif frequency in DLX peaks and red bars in GC-matched background sequences (enrichment in parentheses). (I) Distance from TSS to nearest DLX peak for DE genes by peak stringency. (J) Median Phastcons scores for vertebrate-conserved elements at promoter and distal DLX peaks by stringency.« less

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