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Long non-coding RNA (lncRNA) is a type of regulatory molecule that is not less than 200 nucleotides in length and performs biological functions in the form of RNA
.
Alternative splicing refers to the process of producing RNA isoforms from the same RNA precursor through different splicing methods
.
Studies have shown that alternative splicing of mRNA is ubiquitous in the central nervous system, and the splicing isoforms produced can act in different cells or subcellular regions through specific modes of action, or through specific molecular mechanisms, to affect neuronal effects.
Development, migration, synaptic connections and plasticity play an important role
.
The expression of LncRNA in the central nervous system is very abundant, and it is also generally regulated by alternative splicing.
However, how the alternative splicing isoform participates in the regulation of lncRNA function in the central nervous system remains to be in-depth
.
The cerebellum is an important motor regulation center in the central nervous system, and it is also a brain area that has been paid more attention to in traditional neurobiological research
.
The cerebellum has a distinct structure and is rich in a large number of granular cells.
The synapses established by the parallel fibers projected by granule cell axons and the dendrites of Purkinje cells, the only efferent neuron of the cerebellum, are the main neural circuits for the regulation of cerebellar function [1]
.
At present, the study of lncRNA in the cerebellum has not received widespread attention
.
Both Genome Research of Wang Xiangting's research group in 2017 and Nucleic Acids Research in 2019 found that compared with other brain regions, cerebellar lncRNA is abundantly expressed in mice and non-human primates, and has significantly different expressions.
Mode [2,3]
.
Based on human data, Yang Jianhua's research group at Sun Yat-sen University showed that human cerebellar lncRNA also has significant expression differences from other brain regions [4]
.
On the basis of the preliminary work of the research group, on June 10, 2021, Wang Xiangting's research group published a titled Long non-coding RNA PM maintains cerebellar synaptic integrity and Cbln1 activation via Pax6/Mll1-mediated H3K4me3 on PLOS Biology and published it in the journal The official website is highly recommended [5].
This work takes cerebellar lncRNA research as a key research direction and found that lncRNA-PM (Promoting Methylation), which forms divergent lncRNA with cerebellar peptide Cbln1, plays an important role in the regulation of cerebellar synaptic integrity and motor function Role
.
First, through the development time node detection, expression level interference, FISH experiment, immunofluorescence and luciferase report experiments, Wang Xiangting's group found that lncRNA-PM and Cbln1 co-localized in mouse cerebellar granule cells, and significantly promoted the transcription of Cbln1
.
Through specific knockdown of lncRNA-PM in the mouse cerebellum after birth and subsequent immunofluorescence, electron microscopy, behavioral and other experimental methods, it was found that the synaptic connections in the cerebellum of lncRNA-PM knockdown mice were significantly reduced, and the exercise ability was significant.
Lower
.
By analyzing the histone modification on the Cbln1 promoter, it is found that the Cbln1 promoter is rich in H3K4me3 modifications, and further discovered the Cbln1 transcriptional activation mechanism mediated by lncRNA-PM-Pax6-Mll1-H3K4me3
.
Among them, Pax6 is a highly expressed transcription factor in the cerebellum, and it was recently discovered to be a marker for cerebellar granule cells and their precursor cell population [6]
.
Cbln1 was discovered in 1991.
It is a secreted protein expressed by cerebellar granule cells.
It is also a key factor for constructing and maintaining the synapse integrity between granule cell axons and Purkinje cell dendrites.
It is called cerebellar synaptic organizer.
【7】
.
In sharp contrast to the important function of Cbln1, the regulation mechanism of Cbln1 expression in cerebellar granule cells has not yet been resolved
.
The work of Wang Xiangting's group revealed the regulatory mechanism of Cbln1 transcriptional activation for the first time
.
Interestingly, lncRNA-PM is one of the many splicing isoforms of lncRNA Gm2694
.
In 2019, Wang Yangming's research group at Peking University reported that Gm2694 promotes the self-renewal of embryonic stem cells, the splicing isoform lncRNA-Trincr1 [8]
.
Unlike lncRNA-Trincr1, which is mainly expressed in the cytoplasm, the lncRNA-PM (Gm2694-204) that Wang Xiangting’s research group focused on this time is mainly located in the nucleus
.
Through comparative studies with the other four splicing isoforms of Gm2694, Wang Xiangting's group found that lncRNA-PM has isoform specificity in the transcriptional regulation of Cbln1
.
Under the current situation of further in-depth research on lncRNA, in-depth discussion of the differences of lncRNA isoforms will help to further reveal the molecular mechanism and specific biological functions of lncRNA, and provide important experimental evidence and foundation for comprehensively revealing the mystery of the human genome Theory
.
Jin Yan, a doctoral student at the University of Science and Technology of China, is the first author of the work, and researcher Wang Xiangting from the First Affiliated Hospital of the University of Science and Technology of China is the corresponding author of the work
.
Original link: https://doi.
org/10.
1371/journal.
pbio.
3001297 Platemaker: 11 References 1.
Hibi M, Shimizu T.
Development of the cerebellum and cerebellar neural circuits.
Dev Neurobiol.
2012;72(3 ):282-301.
Epub 2011/02/11.
doi: 10.
1002/dneu.
20875.
PubMed PMID: 21309081.
2.
Liu S, Wang Z, Chen D, Zhang B, Tian RR, Wu J, et al.
Annotation and cluster analysis of spatiotemporal- and sex-related lncRNA expression in rhesus macaque brain.
Genome Res.
2017;27(9):1608-20.
Epub 2017/07/09.
doi: 10.
1101/gr.
217463.
116.
PubMed PMID: 28687705; PubMed Central PMCID: PMCPMC5580719.
3.
Wang F, Ren D, Liang X, Ke S, Zhang B, Hu B, et al.
A long noncoding RNA cluster-based genomic locus maintains proper development and visual function.
Nucleic Acids Res.
2019; 47(12):6315-29.
Epub 2019/05/28.
doi: 10.
1093/nar/gkz444.
PubMed PMID: 31127312; PubMed Central PMCID: PMCPMC6614851.
4.
Zhang XQ,Wang ZL, Poon MW, Yang JH.
Spatial-temporal transcriptional dynamics of long non-coding RNAs in human brain.
Hum Mol Genet.
2017;26(16):3202-11.
Epub 2017/06/03.
doi: 10.
1093/ hmg/ddx203.
PubMed PMID: 28575308.
5.
Jin Y, Zhang B, Lu J, Song Y, Wang W, Zhang W, et al.
Long noncoding RNA PM maintains cerebellar synaptic integrity and Cbln1 activation via Pax6/Mll1-mediated H3K4me3.
Plos Biol.
2021;19(6):e3001297.
Epub 2021/06/11.
doi: 10.
1371/journal.
pbio.
3001297.
PubMed PMID: 34111112.
6.
Carter RA, Bihannic L, Rosencrance C, Hadley JL, Tong YA, Phoenix TN , et al.
A Single-Cell Transcriptional Atlas of the Developing Murine Cerebellum.
Curr Biol.
2018;28(18):2910-+.
doi: 10.
1016/j.
cub.
2018.
07.
062.
PubMed PMID: WOS:000445418500021.
7.
Hirai H, Pang Z, Bao D, Miyazaki T, Li L, Miura E, et al.
Cbln1 is essential for synaptic integrity and plasticity in the cerebellum.
Nat Neurosci.
2005;8(11):1534-41.
Epub 2005/10/20.
doi: 10.
1038/nn1576.
PubMed PMID: 16234806.
8.
Li YP, Duan FF, Zhao YT, Gu KL, Liao LQ, Su HB, et al.
A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells.
Nat Commun.
2019;10.
doi: ARTN 136810.
1038/s41467-019-08911- w.
PubMed PMID: WOS:000462142300001.
(You can swipe up and down to read) Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author owns all legal rights, and offenders must be investigated.
(Swipe up and down to read) Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
(Swipe up and down to read) Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated. .
.
Alternative splicing refers to the process of producing RNA isoforms from the same RNA precursor through different splicing methods
.
Studies have shown that alternative splicing of mRNA is ubiquitous in the central nervous system, and the splicing isoforms produced can act in different cells or subcellular regions through specific modes of action, or through specific molecular mechanisms, to affect neuronal effects.
Development, migration, synaptic connections and plasticity play an important role
.
The expression of LncRNA in the central nervous system is very abundant, and it is also generally regulated by alternative splicing.
However, how the alternative splicing isoform participates in the regulation of lncRNA function in the central nervous system remains to be in-depth
.
The cerebellum is an important motor regulation center in the central nervous system, and it is also a brain area that has been paid more attention to in traditional neurobiological research
.
The cerebellum has a distinct structure and is rich in a large number of granular cells.
The synapses established by the parallel fibers projected by granule cell axons and the dendrites of Purkinje cells, the only efferent neuron of the cerebellum, are the main neural circuits for the regulation of cerebellar function [1]
.
At present, the study of lncRNA in the cerebellum has not received widespread attention
.
Both Genome Research of Wang Xiangting's research group in 2017 and Nucleic Acids Research in 2019 found that compared with other brain regions, cerebellar lncRNA is abundantly expressed in mice and non-human primates, and has significantly different expressions.
Mode [2,3]
.
Based on human data, Yang Jianhua's research group at Sun Yat-sen University showed that human cerebellar lncRNA also has significant expression differences from other brain regions [4]
.
On the basis of the preliminary work of the research group, on June 10, 2021, Wang Xiangting's research group published a titled Long non-coding RNA PM maintains cerebellar synaptic integrity and Cbln1 activation via Pax6/Mll1-mediated H3K4me3 on PLOS Biology and published it in the journal The official website is highly recommended [5].
This work takes cerebellar lncRNA research as a key research direction and found that lncRNA-PM (Promoting Methylation), which forms divergent lncRNA with cerebellar peptide Cbln1, plays an important role in the regulation of cerebellar synaptic integrity and motor function Role
.
First, through the development time node detection, expression level interference, FISH experiment, immunofluorescence and luciferase report experiments, Wang Xiangting's group found that lncRNA-PM and Cbln1 co-localized in mouse cerebellar granule cells, and significantly promoted the transcription of Cbln1
.
Through specific knockdown of lncRNA-PM in the mouse cerebellum after birth and subsequent immunofluorescence, electron microscopy, behavioral and other experimental methods, it was found that the synaptic connections in the cerebellum of lncRNA-PM knockdown mice were significantly reduced, and the exercise ability was significant.
Lower
.
By analyzing the histone modification on the Cbln1 promoter, it is found that the Cbln1 promoter is rich in H3K4me3 modifications, and further discovered the Cbln1 transcriptional activation mechanism mediated by lncRNA-PM-Pax6-Mll1-H3K4me3
.
Among them, Pax6 is a highly expressed transcription factor in the cerebellum, and it was recently discovered to be a marker for cerebellar granule cells and their precursor cell population [6]
.
Cbln1 was discovered in 1991.
It is a secreted protein expressed by cerebellar granule cells.
It is also a key factor for constructing and maintaining the synapse integrity between granule cell axons and Purkinje cell dendrites.
It is called cerebellar synaptic organizer.
【7】
.
In sharp contrast to the important function of Cbln1, the regulation mechanism of Cbln1 expression in cerebellar granule cells has not yet been resolved
.
The work of Wang Xiangting's group revealed the regulatory mechanism of Cbln1 transcriptional activation for the first time
.
Interestingly, lncRNA-PM is one of the many splicing isoforms of lncRNA Gm2694
.
In 2019, Wang Yangming's research group at Peking University reported that Gm2694 promotes the self-renewal of embryonic stem cells, the splicing isoform lncRNA-Trincr1 [8]
.
Unlike lncRNA-Trincr1, which is mainly expressed in the cytoplasm, the lncRNA-PM (Gm2694-204) that Wang Xiangting’s research group focused on this time is mainly located in the nucleus
.
Through comparative studies with the other four splicing isoforms of Gm2694, Wang Xiangting's group found that lncRNA-PM has isoform specificity in the transcriptional regulation of Cbln1
.
Under the current situation of further in-depth research on lncRNA, in-depth discussion of the differences of lncRNA isoforms will help to further reveal the molecular mechanism and specific biological functions of lncRNA, and provide important experimental evidence and foundation for comprehensively revealing the mystery of the human genome Theory
.
Jin Yan, a doctoral student at the University of Science and Technology of China, is the first author of the work, and researcher Wang Xiangting from the First Affiliated Hospital of the University of Science and Technology of China is the corresponding author of the work
.
Original link: https://doi.
org/10.
1371/journal.
pbio.
3001297 Platemaker: 11 References 1.
Hibi M, Shimizu T.
Development of the cerebellum and cerebellar neural circuits.
Dev Neurobiol.
2012;72(3 ):282-301.
Epub 2011/02/11.
doi: 10.
1002/dneu.
20875.
PubMed PMID: 21309081.
2.
Liu S, Wang Z, Chen D, Zhang B, Tian RR, Wu J, et al.
Annotation and cluster analysis of spatiotemporal- and sex-related lncRNA expression in rhesus macaque brain.
Genome Res.
2017;27(9):1608-20.
Epub 2017/07/09.
doi: 10.
1101/gr.
217463.
116.
PubMed PMID: 28687705; PubMed Central PMCID: PMCPMC5580719.
3.
Wang F, Ren D, Liang X, Ke S, Zhang B, Hu B, et al.
A long noncoding RNA cluster-based genomic locus maintains proper development and visual function.
Nucleic Acids Res.
2019; 47(12):6315-29.
Epub 2019/05/28.
doi: 10.
1093/nar/gkz444.
PubMed PMID: 31127312; PubMed Central PMCID: PMCPMC6614851.
4.
Zhang XQ,Wang ZL, Poon MW, Yang JH.
Spatial-temporal transcriptional dynamics of long non-coding RNAs in human brain.
Hum Mol Genet.
2017;26(16):3202-11.
Epub 2017/06/03.
doi: 10.
1093/ hmg/ddx203.
PubMed PMID: 28575308.
5.
Jin Y, Zhang B, Lu J, Song Y, Wang W, Zhang W, et al.
Long noncoding RNA PM maintains cerebellar synaptic integrity and Cbln1 activation via Pax6/Mll1-mediated H3K4me3.
Plos Biol.
2021;19(6):e3001297.
Epub 2021/06/11.
doi: 10.
1371/journal.
pbio.
3001297.
PubMed PMID: 34111112.
6.
Carter RA, Bihannic L, Rosencrance C, Hadley JL, Tong YA, Phoenix TN , et al.
A Single-Cell Transcriptional Atlas of the Developing Murine Cerebellum.
Curr Biol.
2018;28(18):2910-+.
doi: 10.
1016/j.
cub.
2018.
07.
062.
PubMed PMID: WOS:000445418500021.
7.
Hirai H, Pang Z, Bao D, Miyazaki T, Li L, Miura E, et al.
Cbln1 is essential for synaptic integrity and plasticity in the cerebellum.
Nat Neurosci.
2005;8(11):1534-41.
Epub 2005/10/20.
doi: 10.
1038/nn1576.
PubMed PMID: 16234806.
8.
Li YP, Duan FF, Zhao YT, Gu KL, Liao LQ, Su HB, et al.
A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells.
Nat Commun.
2019;10.
doi: ARTN 136810.
1038/s41467-019-08911- w.
PubMed PMID: WOS:000462142300001.
(You can swipe up and down to read) Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author owns all legal rights, and offenders must be investigated.
(Swipe up and down to read) Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
(Swipe up and down to read) Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated. .
