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
- Genetics and Genomics
The establishment and growth of the arterial endothelium requires the coordinated expression of numerous genes. However, regulation of this process is not yet fully understood. Here, we combined in silico analysis with transgenic mice and zebrafish models to characterize arterial-specific enhancers associated with eight key arterial identity genes (Acvrl1/Alk1, Cxcr4, Cxcl12, Efnb2, Gja4/Cx37, Gja5/Cx40, Nrp1 and Unc5b). Next, to elucidate the regulatory pathways upstream of arterial gene transcription, we investigated the transcription factors binding each arterial enhancer compared to a similar assessment of non-arterial endothelial enhancers. These results found that binding of SOXF and ETS factors was a common occurrence at both arterial and pan-endothelial enhancers, suggesting neither are sufficient to direct arterial specificity. Conversely, FOX motifs independent of ETS motifs were over-represented at arterial enhancers. Further, MEF2 and RBPJ binding was enriched but not ubiquitous at arterial enhancers, potentially linked to specific patterns of behaviour within the arterial endothelium. Lastly, there was no shared or arterial-specific signature for WNT-associated TCF/LEF, TGFβ/BMP-associated SMAD1/5 and SMAD2/3, shear stress-associated KLF4 or venous-enriched NR2F2. This cohort of well characterized and in vivo-verified enhancers can now provide a platform for future studies into the interaction of different transcriptional and signalling pathways with arterial gene expression.
