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.
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
The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in Caenorhabditis elegans. Loss of wts-1/LATS, the core kinase of the Hpo pathway, resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner, the downstream transcriptional co-activator of LATS. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule-stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.
