Dlk1-Dio3 locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity

Yen, Yu-Chun; Hsieh, Wen Fu; Tsai, Ya-Yin; Lu, Ya Lin; Liau, Ee Shan; Hsu, Ho Chiang; Chen, Yen‐Chung; Liu, Ting Chun; Chang, Mien; Li, Joye; Lin, Shau Ping; Hung, Jui-Hung; Chen, Jun-An

doi:10.7554/elife.38080

Cited by 47 publications

(50 citation statements)

References 107 publications

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“…Maternally expressed gene 3 (Meg3), results in upregulation of progenitor genes (i.e., Pax6 and Dbx1) in embryonic stem cell (ESC)-derived post-mitotic MNs, as well as in post-mitotic neurons in embryos. Mechanistically, Meg3 associates with the PRC2 complex to facilitate the maintenance of H3K27me3 levels in many progenitor loci, including Pax6 and Dbx1 (Figure 2b) [156]. Apart from lncRNA-mediated regulation of Pax6 in the spinal cord, corticogenesis in primates also seems to rely on the Pax6/lncRNA axis [113,145].…”

Section: Role Of Lncrnas In Regulating Neural Progenitorsmentioning

confidence: 99%

“…However, to date, only one study has established a link between the roles of lncRNAs in MN development and Hox regulation. Using an embryonic stem cell differentiation system, a battery of MN hallmark lncRNAs have been identified [14,156]. Among these MN-hallmark lncRNAs, knockdown of Meg3 leads to the dysregulation of Hox genes whereby caudal Hox gene expression (Hox9~Hox13) is increased but rostral Hox gene expression (Hox1~Hox8) declines in cervical MNs.…”

Section: Lncrnas In the Regulation Of Postmitotic Neuronsmentioning

confidence: 99%

“…Among these MN-hallmark lncRNAs, knockdown of Meg3 leads to the dysregulation of Hox genes whereby caudal Hox gene expression (Hox9~Hox13) is increased but rostral Hox gene expression (Hox1~Hox8) declines in cervical MNs. Analysis of maternally-inherited intergenic differentially methylated region deletion (IG-DMR matΔ ) mice in which Meg3 and its downstream transcripts are further depleted has further revealed ectopic expression of caudal Hoxc8 in the rostral Hoxa5 region of the brachial segment, together with a concomitant erosion of Hoxmediated downstream genes and axon arborization (Figure 2b) [156]. Given that dozens of lncRNAs have been identified as hallmarks of postmitotic MNs, it remains to be determined if these other lncRNAs are functionally important in vivo.…”

Section: Lncrnas In the Regulation Of Postmitotic Neuronsmentioning

confidence: 99%

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Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease

Chen

2020

J Biomed Sci

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Long non-coding RNAs (lncRNAs) have gained increasing attention as they exhibit highly tissue-and cell-type specific expression patterns. LncRNAs are highly expressed in the central nervous system and their roles in the brain have been studied intensively in recent years, but their roles in the spinal motor neurons (MNs) are largely unexplored. Spinal MN development is controlled by precise expression of a gene regulatory network mediated spatiotemporally by transcription factors, representing an elegant paradigm for deciphering the roles of lncRNAs during development. Moreover, many MN-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are associated with RNA metabolism, yet the link between MN-related diseases and lncRNAs remains obscure. In this review, we summarize lncRNAs known to be involved in MN development and disease, and discuss their potential future therapeutic applications.

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Section: Role Of Lncrnas In Regulating Neural Progenitorsmentioning

confidence: 99%

Section: Lncrnas In the Regulation Of Postmitotic Neuronsmentioning

confidence: 99%

Section: Lncrnas In the Regulation Of Postmitotic Neuronsmentioning

confidence: 99%

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Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease

Chen

2020

J Biomed Sci

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“…Expression of canonically imprinted genes, such as Peg10, Meg3, Grb10, and Snrpn, show the lowest degree of context-specificity across all tissues. This likely reflects the fundamental role of these genes in growth and development [53][54][55][56] . Although these parent-of-origin dependent allele-specific expression biases are consistent with imprinting mechanisms, we cannot rule out that maternal and/or paternal effects also contribute to the phenomena we observe.…”

Section: Discussionmentioning

confidence: 95%

Epistatic Networks Associated with Parent-of-Origin Effects on Metabolic Traits

Macias-Velasco¹,

Pierre²,

Wayhart³

et al. 2019

Preprint

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Parent-of-origin effects (POE) are unexpectedly common in complex traits, including metabolic and neurological diseases. POE can also be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific POE on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these POE phenomena.Here, we use a simple yet powerful F1 reciprocal cross model to test the hypothesis that non-imprinted genes can generate complex POE on metabolic traits through genetic interactions with imprinted genes.Male and female mice from a F1 reciprocal cross of LG/J and SM/J strains were fed either high or low fat diets. We generated expression profiles from three metabolically-relevant tissues: hypothalamus, white adipose, and liver. We identified two classes of parent-of-origin expression biases: genes showing parent-of-origin-dependent allele-specific expression and biallelic genes that are differentially expressed by reciprocal cross. POE patterns of both gene classes are highly tissue-and context-specific, sometimes occurring only in one sex and/or diet cohort in a particular tissue. We then constructed tissue-specific interaction networks among genes from these two classes of POE. A key subset of gene pairs show significant epistasis in the F16 LG/J x SM/J advanced intercross data in cases where the biallelic gene fell within a previously-identified metabolic POE QTL interval. We highlight one such interaction in adipose, between Nnat and Mogat1, which associates with POE on multiple adiposity traits. Both genes localize to the endoplasmic reticulum of adipocytes and play a role in adipogenesis. Additionally, expression of both genes is significantly correlated in human visceral adipose tissue. The genes and networks we present here represent a set of actionable interacting candidates that can be probed to further identify the machinery driving POE on complex traits. Parent-of-origin effects, where an allele's phenotypic effect depends on whether it is inherited maternally or paternally, are associated with a wide range of common complex traits and diseases 1 .Several mechanisms can cause parent-of-origin effects on phenotype including genomic imprinting, maternal/paternal effects, and sex-biased gene-specific trinucleotide expansions 2-4 . The best characterized parent-of-origin effect on phenotype is genomic imprinting, an epigenetic process in which either the maternally or paternally inherited allele is silenced. Parent-of-origin effects are often associated with diseases related to metabolism, neurological function, or both. Metabolic diseases include transient neonatal diabetes 5-8 , type-1 diabetes 9 , type-2 diabetes 10,11 , some cancers 12,13 , metabolic syndrome, Beckwith-Wiedemann syndrome, Wilm's tumors 14 , insulinomas 12 , Si...

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“…Examples of trans-effects have been reported for the lncRNAs Fendrr essential for proper heart development and Pint important in cell proliferation, both of which recruit the PRC2 complex for H3K27 tri-methylation of loci located on other chromosomes 43,44 . Another lncRNA, Meg3, recruits two PRC2 components, JARID2 and EZH2, to facilitate H3K27me3 deposition and repression of specific genes in trans 45,46 . Interestingly, Meg3 has an additional cis-activating role, by sequestration of PRC2 to prevent DNA methylation-induced repression of genes within the Meg3-Mirg imprinting cluster 47,48 .…”

Section: Discussionmentioning

confidence: 99%

Trans- and cis-acting effects of the lncRNA Firre on epigenetic and structural features of the inactive X chromosome

Bonora

Lewandowski

et al. 2019

Preprint

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Firre encodes a lncRNA involved in nuclear organization in mammals. Here we find that Firre RNA is transcribed from the active X chromosome (Xa) and exerts trans-acting effects on the inactive X chromosome (Xi). Allelic deletion of Firre on the Xa in a mouse hybrid fibroblast cell line results in a dramatic loss of the histone modification H3K27me3 and of components of the PRC2 complex on the Xi as well as the disruption of the perinucleolar location of the Xi. These features are measurably rescued by ectopic expression of a mouse or human Firre/FIRRE cDNA transgene, strongly supporting a conserved trans-acting role of the Firre transcript in maintaining the Xi heterochromatin environment. Surprisingly, CTCF occupancy is decreased on the Xi upon loss of Firre RNA, but is partially recovered by ectopic transgene expression, suggesting a functional link between Firre RNA and CTCF in maintenance of epigenetic features and/or location of the Xi.Loss of Firre RNA results in dysregulation of genes implicated in cell division and development, but not in reactivation of genes on the Xi, which retains its bipartite structure despite some changes in chromatin contact distribution. Allelic deletion or inversion of Firre on the Xi causes localized redistribution of chromatin contacts, apparently dependent on the orientation of CTCF binding sites clustered at the locus. Thus, the Firre locus and its RNA have roles in the maintenance of epigenetic features and structure of the Xi. X chromosome inactivation (XCI) is controlled by the X-inactivation center that contains the long noncoding RNA (lncRNA) locus Xist and some of its regulators such as Tsix, Jpx and Ftx 1,2 . At the onset of XCI, Xist becomes highly expressed on one allele, and the lncRNA coats the future inactive X chromosome (Xi) in cis [3][4][5] . Specific proteins are recruited by Xist RNA, while others are removed to mediate serial layers of epigenetic modifications, resulting in gene silencing and heterochromatin formation [6][7][8] . Epigenetic hallmarks of the Xi include hypo-acetylation of histones H3 and H4, ubiquitination of histone H2A at lysine 119 (H2AK119ubi), de-methylation of histone H3 at lysine 4, tri-methylation of histone H3 at lysine 27 (H3K27me3), di-and trimethylation of histone H3 at lysine 9 (H3K9me2/3), mono-methylation of histone H4 at lysine 20 (H4K20me), and enrichment in the histone variant macroH2A 9 . Additional layers of control ensure stability of the silent state of the Xi, including DNA methylation of promoter-containing CpG islands, spatial reorganization of the Xi within the nucleus, and a shift to late replication 10,11 .The Xi appears as a heteropycnotic Barr body within the interphase nucleus where it is usually located close to either the nuclear lamina or the periphery of the nucleolus 12-16 . These two locations are preferred sites of heterochromatin, not only for the Xi but also for other repressed regions of the genome, suggesting that the lamina and the nucleolus play important roles in maintenance of silent chromatin 12...

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Dlk1-Dio3 locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity

Cited by 47 publications

References 107 publications

Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease

Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease

Epistatic Networks Associated with Parent-of-Origin Effects on Metabolic Traits

Trans- and cis-acting effects of the lncRNA Firre on epigenetic and structural features of the inactive X chromosome

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