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.
Reviewing Editor
- Alejandro Sánchez Alvarado, Stowers Institute for Medical Research, United States
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.
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
- Evolutionary Biology
Despite rapid evolution across eutherian mammals, the X-linked MIR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (SLITRK2 and FMR1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked MIR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernible defects, but simultaneous ablation of five clusters containing 19 members of the MIR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility, and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked MIR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the MIR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.
