Dlk1-Dio3 locus-derived LncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity
- Academia Sinica, Taiwan, Republic of China
- National Chiao Tung University, Taiwan, Republic of China
- National Taiwan University, Taiwan, Republic of China
Abstract
The mammalian imprinted Dlk1-Dio3 locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, including Meg3 (i.e., Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By profiling cell types at each stage of embryonic stem cell derived motor neurons (ESC~MNs) that recapitulate spinal cord development, we uncovered that lncRNAs expressed from the Dlk1-Dio3 locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically, Meg3 and other Dlk1-Dio3 locus-derived lncRNAs facilitate Ezh2/Jarid2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudal Hox genes in postmitotic MNs. Our data thus illustrate that these lncRNAs in the Dlk1-Dio3 locus, particularly Meg3, play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulating Hox genes.
Data availability
All microarray, RNA-seq, ChIP-seq data have been deposited in GEO under accession codes GSE114283, GSE114285 and GSE114228.
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Genome-wide maps of H3K27me3 in chromatin state in embryonic stem cells differentiated motor neuronsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE114283).
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Next Generation Sequencing Facilitates Quantitative Analysis of ES, pMN, MN, and IN TranscriptomesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE114285).
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Transcriptome analysis of Meg3 KD and IG-DMR maternal deletion in ESC, pMN, and MNPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE114228).
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Induced V5-tagged Lhx3 (iLhx3-V5) in iNIL3-induced motor neurons (Day 4)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM782847).
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Isl1/2 in iNIL3-induced motor neurons (Day 4)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM782848).
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H3K4me3Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1468401).
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H3K27ac_day6Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM2098385).
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ATAC_seq_day6Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM2098391).
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RAR_Day2+8hrsRAPublicly available at the NCBI Gene Expression Omnibus (accession no: GSM482750).
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Pol2-S5P_Day2+8hPublicly available at the NCBI Gene Expression Omnibus (accession no: GSM981593).
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ES-WTPublicly available at the NCBI Gene Expression Omnibus (accession no: GSM2420680).
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AK4-WTPublicly available at the NCBI Gene Expression Omnibus (accession no: GSM2420683).
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AK7-WTPublicly available at the NCBI Gene Expression Omnibus (accession no: GSM2420684).
Article and author information
Author details
Funding
Ministry of Science and Technology, Taiwan (RO1)
- Jun-An Chen
National Health Research Institutes (CDG)
- Jun-An Chen
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 of the live animals were kept in an SPF animal facility, approved and overseen by IACUC (12-07-389 ) Academia Sinica.
Reviewing Editor
- Alejandro Sánchez Alvarado, Stowers Institute for Medical Research, United States
Version history
- Received: May 3, 2018
- Accepted: October 11, 2018
- Accepted Manuscript published: October 12, 2018 (version 1)
- Version of Record published: November 7, 2018 (version 2)
- Version of Record updated: February 5, 2020 (version 3)
Copyright
© 2018, Yen 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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Dlk1-Dio3 locus-derived LncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity
eLife 7:e38080.
https://doi.org/10.7554/eLife.38080
Further reading
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- Developmental Biology
- Neuroscience
Development of the nervous system depends on signaling centers – specialized cellular populations that produce secreted molecules to regulate neurogenesis in the neighboring neuroepithelium. In some cases, signaling center cells also differentiate to produce key types of neurons. The formation of a signaling center involves its induction, the maintenance of expression of its secreted molecules, and cell differentiation and migration events. How these distinct processes are coordinated during signaling center development remains unknown. By performing studies in mice, we show that Lmx1a acts as a master regulator to orchestrate the formation and function of the cortical hem (CH), a critical signaling center that controls hippocampus development. Lmx1a co-regulates CH induction, its Wnt signaling, and the differentiation and migration of CH-derived Cajal–Retzius neurons. Combining RNAseq, genetic, and rescue experiments, we identified major downstream genes that mediate distinct Lmx1a-dependent processes. Our work revealed that signaling centers in the mammalian brain employ master regulatory genes and established a framework for analyzing signaling center development.
