Long noncoding RNA PM maintains cerebellar synaptic integrity and Cbln1 activation via Pax6/Mll1-mediated H3K4me3

Yan Jin; Bowen Zhang; Junxia Lu; Yingdong Song; Wei Wang; Wei Zhang; Fanghong Shao; Meng Gong; Meiting Wang; Xiaolin Liang; Shuqin Li; Zhi Zhang; Ge Shan; Xiangting Wang

doi:10.1371/journal.pbio.3001297

Long noncoding RNA PM maintains cerebellar synaptic integrity and Cbln1 activation via Pax6/Mll1-mediated H3K4me3

PLoS Biol. 2021 Jun 10;19(6):e3001297. doi: 10.1371/journal.pbio.3001297. eCollection 2021 Jun.

Authors

Yan Jin^{1

2

3}, Bowen Zhang^{1

2

3}, Junxia Lu^{1

2

3}, Yingdong Song^{1

2

3}, Wei Wang^{1

2

3}, Wei Zhang^{3

4}, Fanghong Shao^{1

2

3}, Meng Gong^{1

2

3}, Meiting Wang^{5

6}, Xiaolin Liang^{1

2

3}, Shuqin Li⁷, Zhi Zhang^{3

6

8}, Ge Shan^{3

4}, Xiangting Wang^{1

2

3}

Affiliations

¹ Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
² Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, China.
³ Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China.
⁴ The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁵ Liren College, Yanshan University, Qinhuangdao, China.
⁶ Department of Neurobiology and Biophysics, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁷ Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China.
⁸ Department of Anesthesiology, The First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Abstract

Recent studies have shown that long noncoding RNAs (lncRNAs) are critical regulators in the central nervous system (CNS). However, their roles in the cerebellum are currently unclear. In this work, we identified the isoform 204 of lncRNA Gm2694 (designated as lncRNA-Promoting Methylation (lncRNA-PM)) is highly expressed in the cerebellum and derived from the antisense strand of the upstream region of Cerebellin-1 (Cbln1), a well-known critical cerebellar synaptic organizer. LncRNA-PM exhibits similar spatiotemporal expression pattern as Cbln1 in the postnatal mouse cerebellum and activates the transcription of Cbln1 through Pax6/Mll1-mediated H3K4me3. In mouse cerebellum, lncRNA-PM, Pax6/Mll1, and H3K4me3 are all associated with the regulatory regions of Cbln1. Knockdown of lncRNA-PM in cerebellum causes deficiencies in Cbln1 expression, cerebellar synaptic integrity, and motor function. Together, our work reveals an lncRNA-mediated transcriptional activation of Cbln1 through Pax6-Mll1-H3K4me3 and provides novel insights of the essential roles of lncRNA in the cerebellum.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing / genetics
Cerebellum / metabolism
Gene Expression Regulation
HEK293 Cells
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Histones / metabolism*
Humans
Motor Activity
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism*
Nerve Tissue Proteins / metabolism*
Neurons / metabolism
PAX6 Transcription Factor / metabolism*
Presynaptic Terminals / metabolism
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Precursors / metabolism*
RNA, Long Noncoding / genetics
RNA, Long Noncoding / metabolism*
Synapses / metabolism*
Transcriptional Activation / genetics

Substances

Cbln1 protein, mouse
Histones
Nerve Tissue Proteins
PAX6 Transcription Factor
Protein Isoforms
Protein Precursors
RNA, Long Noncoding
histone H3 trimethyl Lys4
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
Kmt2a protein, mouse

Grants and funding

This research was funded by the National Key Research and Development Program of China (http://www.most.gov.cn; 2016YFC1000605 to XW and 2019YFA0802600 to GS) and National Natural Science Foundation of China (http://www.nsfc.gov.cn; 31671306 to XW), Anhui Mental Health Center (http://www.ahmhcentre.com; 2019LH01 to XW), and the Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology (http://cpst.ustc.edu.cn; 2018CXFX006 to XW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.