. 2017 Nov 2;171(4):877-889.e17.

doi: 10.1016/j.cell.2017.09.003. Epub 2017 Sep 28.

Temporal Control of Mammalian Cortical Neurogenesis by m⁶A Methylation

Ki-Jun Yoon¹, Francisca Rojas Ringeling², Caroline Vissers³, Fadi Jacob⁴, Michael Pokrass³, Dennisse Jimenez-Cyrus⁵, Yijing Su⁶, Nam-Shik Kim⁷, Yunhua Zhu⁸, Lily Zheng², Sunghan Kim⁸, Xinyuan Wang⁶, Louis C Doré⁹, Peng Jin¹⁰, Sergi Regot¹¹, Xiaoxi Zhuang¹², Stefan Canzar¹³, Chuan He⁹, Guo-Li Ming¹⁴, Hongjun Song¹⁵

Affiliations

¹ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² The Pre-doctoral Human Genetic Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Departments of Chemistry and Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
¹⁰ Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
¹¹ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹² Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.
¹³ Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
¹⁴ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@pennmedicine.upenn.edu.
¹⁵ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Pre-doctoral Human Genetic Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@pennmedicine.upenn.edu.

PMID: 28965759
PMCID: PMC5679435
DOI: 10.1016/j.cell.2017.09.003

Temporal Control of Mammalian Cortical Neurogenesis by m⁶A Methylation

Ki-Jun Yoon et al. Cell. 2017.

. 2017 Nov 2;171(4):877-889.e17.

doi: 10.1016/j.cell.2017.09.003. Epub 2017 Sep 28.

Authors

Affiliations

¹ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² The Pre-doctoral Human Genetic Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Departments of Chemistry and Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
¹⁰ Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
¹¹ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹² Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.
¹³ Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
¹⁴ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@pennmedicine.upenn.edu.
¹⁵ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Pre-doctoral Human Genetic Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@pennmedicine.upenn.edu.

PMID: 28965759
PMCID: PMC5679435
DOI: 10.1016/j.cell.2017.09.003

Abstract

N⁶-methyladenosine (m⁶A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m⁶A regulates mammalian brain development is unknown. Here, we show that m⁶A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m⁶A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m⁶A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m⁶A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m⁶A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m⁶A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m⁶A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.

Keywords: Mettl14; RNA methylation; autism; epitranscriptomics; human organoid; m(6)A; neurogenesis; radial glia cell; schizophrenia; transcriptional prepatterning.

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Figures

**Figure 1. Nervous system *Mettl14* deletion results in residual radial glia cells and ongoing neurogenesis in the postnatal mouse cortex**
(A–C) Presence of neurogenic RGCs in P5 *Nestin-Cre;Mettl14^f/f* cKO cortices. Shown are sample confocal images (A, B) and quantifications (C). Regions in white boxes are shown at a higher magnification. Scale bars: 500 μm (A, top panel), 50 μm (A, bottom panel), 100 μm (B). Values in (C) represent mean ± SEM (n = 4–7; ***: P < 0.001; *: *P <* 0.05; unpaired Student’s t-test). (D–E) Presence of IPCs in P5 cKO cortices. Shown are sample confocal images (D; scale bars: 100 μm) and quantification (E). Values represent mean ± SEM (n = 6; ***: P < 0.001; **: *P <* 0.01; unpaired Student’s t-test). (F–G) Ongoing neurogenesis in P5 cKO cortices. P5 pups were injected with EdU and analyzed 48 hr later. Shown in (F) are sample confocal images of the ventricular side of the primary somatosensory cortex. Arrows indicate Pax6⁺EdU⁺ cells (top) and Tbr2⁺TuJ1⁺EdU⁺ cells (bottom). Scale bars: 100 μm. Quantification of EdU⁺ cells with different markers is shown in (G). Values represent mean ± SEM (n = 6; ***: P < 0.001; unpaired Student’s t-test). (H–K) Reduced production of upper-layer neurons and astrocytes in cKO cortices. Pregnant mice were injected with EdU at E15.5 and analyzed at P5. Shown are sample confocal images (H, J; scale bars: 100 μm) and quantification (I, K). Values represent mean ± SEM (n = 6; ***: P < 0.001; unpaired Student’s t-test). See also Figure S1

**Figure 2. *Mettl14^−/−* RGCs and NPCs exhibit prolonged cell cycle progression**
(A–B) Abnormal INM of RGCs in *Mettl14* cKO cortices. Pregnant mice were injected with EdU at E17.5 and analyzed 0.5 or 6 hr later. Shown are sample confocal images (A; scale bars: 50 μm) and quantification of the distance from Pax6⁺EdU⁺ nuclei to the ventricular surface (B). Values for the percentages of nuclei in each 20 μm bin represent mean ± SEM (n = 4; ***: P < 0.001; **: *P <* 0.01; *: *P <* 0.05; unpaired Student’s t-test). (C–D) Delayed S to M phase transition of RGCs in *Mettl14* cKO mice. Pregnant mice were injected with EdU at E17.5 and analyzed 2 hr later. Shown in (C) are sample confocal images. Arrowheads point to Pax6⁺pH3⁺EdU⁺ cells and arrows point to Pax6⁺pH3⁺EdU⁻ cells. Scale bar: 50 μm. Shown in (D) is the quantification of the percentage of Pax6⁺pH3⁺EdU⁺ cells, representing cells proceeded from S to M phase during the 2 hr chase, among total Pax6⁺pH3⁺ cells. Values represent mean ± SEM (n = 5 for WT and n = 8 for cKO; ***: P < 0.001; unpaired Student’s t-test). (E–F) Delayed cell cycle exit of neural progenitors in *Mettl14* cKO mice. Pregnant mice were injected with EdU at E17.5 and analyzed 24 hr later. Shown in (E) are sample confocal images. Arrowheads point to Ki67⁻EdU⁺ cells and arrows point to Ki67⁺EdU⁻ cells. Scale bar: 50 μm. Shown in (F) is the quantification of the percentage of Ki67⁻EdU⁺ cells, representing cells exited from cell cycle, among total EdU⁺ cells. Values represent mean ± SEM (n = 6; ***: P < 0.001; unpaired Student’s t-test). (G–J) Time-lapse imaging analysis of mouse NPCs showing prolonged S-G₂-M phase length in the absence of *Mettl14*. WT and cKO mouse NPCs were electroporated with plasmid co-expressing a Cdk2 sensor (green) and the H2B-mCherry nuclear marker (red), cultured for 2 days, and imaged for 48 hr. Shown in (G) are sample time-lapse images with time stamps. Scale bars: 10 μm. Also shown are box plots of quantifications for the total cell cycle length (H; n = 38 for WT and n = 30 for cKO), G₁ phase length (I; n = 20), and S-G₂-M phase length (J; n = 20). Each dot represents data from one NPC (***: P < 0.001; unpaired Student’s t-test). See also Figure S2.

**Figure 3. Mettl3 regulates cell cycle progression of NPCs and maintenance of embryonic cortical RGCs**
(A) Depletion of m⁶A-tagging on mRNAs purified from E15.5 and E17.5 *Mettl14* cKO mouse forebrain. Shown in the left panels are sample images of m⁶A dot blot and methylene blue staining (for loading controls). Data were normalized to the averaged levels of WT samples and quantification is shown in the right panel. Values represent mean ± SEM (n = 3; **: *P <* 0.01; unpaired Student’s t-test). (B) Depletion of m⁶A-tagging on mRNAs purified from *Mettl14* cKO NPCs. Values represent mean ± SEM (n = 3; **: *P <* 0.01; unpaired Student’s t-test). (C–D) Flow cytometry analysis of cell cycle status of mouse NPCs. NPCs were electroporated to co-express GFP and the control shRNA, or the shRNA against *Mettl3*. At day 4, NPCs were pulse-labeled with EdU (10 μM) for 30 min, cultured for 9 hr, followed by EdU and DNA content (DyeCycle Violet) staining and flow cytometry analysis. Shown are sample histograms of DNA content from GFP⁺EdU⁺ cells and the total cell population (as a reference; C) and quantification (D). Values in (D) represent mean ± SEM (n = 4; **: *P <* 0.01; unpaired Student’s t-test). (E–G) Embryonic mouse cortices were electroporated in utero at E13.5 to co-express GFP and shRNA-control, or GFP and shRNA-Mettl3, and analyzed at E17.5. Shown in (E) are sample confocal images. Scale bars: 50 μm. The distribution of GFP⁺ cells in each zone (F) and the percentage of GFP⁺Pax6⁺ cells among total GFP⁺ cells (G) were quantified. VZ: ventricular zone; SVZ: subventricular zone; IZ: intermediate zone; CP: cortical plate. Values represent mean ± SEM (n = 4; ***: P < 0.001; **: P < 0.01; unpaired Student’s t-test). See also Figure S3.

**Figure 4. m⁶A tags transcripts related to transcription factors, cell cycle, and neuronal differentiation in the embryonic mouse brain, and promotes their decay**
(A) Coverage plots from m⁶A-seq of E13.5 mouse forebrains showing representative examples of m⁶A-tagged (*Sox1*, *Emx2*, and *Cdk9*) and non m⁶A-tagged (*Rad17*) transcripts. Top and middle panels show read coverages normalized by library sizes from m⁶A pulled-down and input libraries, respectively, and bottom panels show gene structures (arrows point to the direction of transcription; S.C.: stop codon). (B–C) GO analysis of m⁶A-tagged genes reveals enrichment for biological process terms related to transcription factors, neurogenesis, cell cycle, and stem cell differentiation. Also shown is Wikipathways gene set enrichment analysis. FDR: false discovery rate. (D) Cumulative distribution of Log₂(gene expression ratios) at time 5 hr post ActD over time 0 hr for m⁶A tagged genes (purple line) and non-m⁶A tagged genes (black line) for WT and *Mettl14* cKO NPCs. D = value of Kolmogorov Smirnov test statistic corresponding to maximum difference between methylated and non-methylated distributions. (E) Cumulative distribution of log₂(fold change in ratios of gene expression) at 5 hr post ActD treatment over time 0 hr upon *Mettl14* deletion. Top panel shows cumulative distribution for non-targets (black line) and transcripts with 1–1.9 m⁶A sites on average (bright red line), or 2 or more sites on average (dark red line). Bottom panel shows cumulative distribution for non-targets and m⁶A-tagged transcripts with 1–2, 2–3, 3–4, and 4 or more sites on average. (F) Summary of half-life of a group of transcripts in WT and *Mettl14* cKO NPCs. Values represent mean ± SEM (n = 4; ***: P < 0.001; **: P < 0.01; unpaired Student’s t-test See also Figure S4, and Table S2, S3 and S4.

**Figure 5. Post-transcriptional regulation of pre-patterning gene levels and protein production by m⁶A signaling in cortical neural stem cells**
(A) Coverage plots from m⁶A-seq of E13.5 mouse forebrains showing representative examples of m⁶A-tagged IPC (*Tbr2* and *Neurog2*) and neuronal (*Neurod1* and *Neurod2*) genes. (B) Q-PCR analysis of total mRNA and 4sU-purified nascent mRNA from WT and *Mettl14* cKO NPCs. All Ct values were first normalized to *Gapdh* control (not m⁶A-tagged), which were similar in both WT and cKO NPCs. The ratio (cKO over WT) was calculated for each experiment and values represent mean ± SEM (n = 3 cultures; ***: P < 0.001; **: *P <* 0.01; *: *P <* 0.05; unpaired Student’s t-test). (C–F) Precocious expression of Tbr2 and Neurod1 proteins in RGCs in E17.5 *Mettl14* cKO mice in vivo. Shown are sample confocal images (C, E; scale bars: 50 μm) and quantifications of the percentage of Tbr2⁺Pax6⁺ cells (D), or Neurod1⁺Pax6⁺ cells (F), among total Pax6⁺ cells (left panels, n = 6) and the density distribution of Tbr2⁺Pax6⁺ (D), or Neurod1⁺Pax6⁺ cells (F), from the ventricular surface (right panels, n = 4). Arrows indicate Tbr2⁺Pax6⁺ (C) or Neurod1⁺Pax6⁺ cells (E). Values in (D, F) represent mean ± SEM (***: P < 0.001; **: *P <* 0.01; *: *P <* 0.05; unpaired Student’s t-test). See also Figure S5.

**Figure 6. METTL14 regulates cell cycle progression of human NPCs**
(A–B) Flow cytometry analysis of cell cycle progression of hNPCs with *METTL14* KD. Human NPCs were electroporated to co-express GFP and shRNA-control, or shRNA-METTL14. After 4 days, hNPCs were pulse-labeled with EdU (10 μM) for 30 min, incubated for 14 hr, followed by EdU and DNA content (DyeCycle Violet) staining and flow cytometry analysis, similarly as in Figure 3C–D. Values represent mean ± SEM (n = 4; **: P < 0.01; unpaired Student’s t-test). (C–D) Flow cytometry analysis of cell cycle progression with *METTL14* KD in human forebrain organoids. Day 45 forebrain organoids were electroporated to co-express GFP and shRNA-control, or shRNA-*METTL14*. After 7 days, forebrain organoids were pulse-labeled with EdU (10 μM) for 1 hr, cultured further for 14 hr, followed by dissociation and analysis similarly as in Figure 3C–D. Values represent mean ± SEM (n = 4; ***: P < 0.001; unpaired Student’s t-test). See also Figure S6.

**Figure 7. Conserved and unique features of m⁶A mRNA methylation in human forebrain organoids, human fetal brain and embryonic mouse forebrain**
(A) Representative plots of two m⁶A-tagged transcripts in day 47 human forebrain organoids and PCW11 human fetal brain, but not in mouse E13.5 forebrain. (B) Venn diagram showing shared m⁶A-tagged transcripts between day 47 human forebrain organoids and PCW11 fetal human brain. (C) GO and disease ontology analyses of shared m⁶A-tagged genes in day 47 human forebrain organoids and PCW11 human fetal brain. (D) Venn diagram showing shared and unique m⁶A-tagged transcripts among mouse E13.5 forebrain, day 47 human forebrain cortex, and PCW11 fetal human brain. Only ortholog genes expressed in all three samples were used for analysis. (E–F) Disease ontology analysis of transcripts uniquely m⁶A-tagged in human shows enrichment for neurodevelopmental diseases, whereas disease ontology analysis of commonly m⁶A-tagged transcripts showed enrichment for oncogenic processes. See also Figure S7, and Table S2 and S5.

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Comment in

Epimetronomics: m6A Marks the Tempo of Corticogenesis.
Boles NC, Temple S. Boles NC, et al. Neuron. 2017 Nov 15;96(4):718-720. doi: 10.1016/j.neuron.2017.11.002. Neuron. 2017. PMID: 29144970
Layered-up regulation in the developing brain.
Sweatt JD. Sweatt JD. Nature. 2017 Nov 23;551(7681):448-449. doi: 10.1038/d41586-017-07269-7. Nature. 2017. PMID: 29168827 Free PMC article.

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Temporal Control of Mammalian Cortical Neurogenesis by m⁶A Methylation

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Temporal Control of Mammalian Cortical Neurogenesis by m⁶A Methylation

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