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An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior

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Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior.

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Figure 1: Morphological changes in cortical neurons induced by developmental nicotine exposure.
Figure 2: Nicotine exposure during development alters expression of a gene involved in histone methylation.
Figure 3: Differential enrichment of H3K4me3 at promoter sites associated with synapse function following developmental nicotine exposure.
Figure 4: The Ash2l–Mef2c complex is regulated by nAChR activity.
Figure 5: The Ash2l–Mef2c complex mediates dendritic remodeling by nicotine in neural progenitor cells and in vivo.
Figure 6: Developmental nicotine-induced changes in passive avoidance behavior require expression of Ash2l and Mef2c.

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  • 20 June 2016

    In the version of this article initially published online, the affiliations of Qiaoping Yuan and David Goldman were switched with those of Angelique Bordey. The error has been corrected for the print, PDF and HTML versions of this article.


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This work was supported by grants DA14241 (M.R.P.), DA10455 (M.R.P.), NS052519 (F.H.) and NS086329 (F.H.) from the National Institutes of Health, the State of Connecticut, Department of Mental Health and Addiction Services and the Kavli Institute for Neuroscience at Yale.

Author information

Authors and Affiliations



Y.J. designed the study, performed the experiments and data analyses, and wrote and edited the manuscript. Z.Z. and Q.Y. prepared samples and analyzed data for the ChIP-seq experiments. D.G. provided critical resources, experimental design and advice on the ChIP-seq experiments. D.C. performed the imaging studies and data analyses for the diffusion tensor imaging experiments. F.H. provided valuable resources and critical advice on interpretation of the diffusion tensor imaging experiments. Y.S.M. designed shRNA constructs, helped troubleshoot knockdown studies and provided critical advice on behavioral design. A.B. provided critical resources, experimental design and advice on the in utero electroporation studies. L.S.H. performed in utero electroporation studies. A.M.L. performed in utero electroporation surgeries and contributed to data collection. C.J.H. designed and prepared samples for the diffusion tensor imaging experiment and contributed to the microarray experiment. M.R.P. designed the project, assisted in interpretation of all studies, and wrote and edited the manuscript. All authors contributed to editing of the manuscript.

Corresponding author

Correspondence to Marina R Picciotto.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Effects of nicotine exposure from birth to 3 weeks of age on dendritic complexity across cortical regions assessed at 3 months of age.

(a-c) Sholl analysis of the apical dendritic tree in frontal (F), parietal (P) and occipital (O) regions of cortex. Exposure to nicotine in the postnatal period significantly increased dendritic complexity across cortical regions. (a) F(1,80)=6.901, p=0.010321. (b) F(1,30)=16.525; p=0.0000001. (c) F(1,65)=32.586, p=0.000319. (d-f) Layer-specific effects of postnatal-only nicotine exposure on dendritic complexity in superficial (1/2), intermediate (3/4) and deep (5/6) layers of cortex. (d) F(1,20) = 5.625, p=0.027854. (e) F(1,46)=13.719, p=0.000565. (f) F(1, 23)=10.746, p=0.003299. *, p < 0.05. F: Sac, n=28; Nic, n=54; P: Sac, n=36; Nic, n=31; O: Sac, n=20; Nic, n=12; 1/2: Sac, n=9; Nic, n=13; 3/4: Sac, n=18, Nic, n=30; 5/6: Sac, n=10. Nic, n=15.

Supplementary Figure 2 Volcano plot showing all probe sets evaluated in the microarray study.

(a) Genes whose expression levels were significantly different between developmentally nicotine exposed animals and controls are shown as red dots. (b) 6 of 15 probe sets were significantly altered in independent samples at 3 months of age following nicotine treatment throughout the pre- and postnatal period compared to the control group: F(1,8)=7.77 for Ash2l, p=0.02365035; F(1,8)=6.797 for Chsy3, p=0.03127061; F(1,8)=0.64 for Zfp91, p=0.44681333; F(1,8)=0.41 for Cflar, p=0.53987164; F(1,8)=26.538 for Zcchc11, p=0.00087271; F(1,8)=5.18 for Cep192, p=0.05240060; F(1,8)=1.24 for Alkbh1, p=0.29780695; F(1,8)=0.72 for Gmeb1, p=0.42080639; F(1,8)=0.36 for Unc13b, p=0.56511006; F(1,8)=0.035 for Duox1, p=0.85625319; F(1,8)=8.82 for Scula2, p=0.01787528; F(1,8)=1.84 for Zfp597, p=0.21198878; F(1,8)=1.18 for Ctnnal1, p=0.30899997; F(1,8)=0.65 for Ntrk, p=0.44341660; F(1,8)=7.397 for Tmem107, p=0.02625917. (*p <0.05, ** p <0.01 with Sidak’s test; # p <0.05 with LSD test for multiple comparisons). 2 to 4 animals were pooled for each biological replicate. Five Biological replicates were used for each condition (Sac: n = 5; Nic: n = 5). A total of 26 animals were used (Sac: n = 14;Nic: n = 12).

Supplementary Figure 3 Changes in H3K4me3 associated with the promoter sites of multiple gene loci following developmental nicotine exposure.

(a) Gene ontology (GO) analysis identified significantly regulated gene groups, all of which are related to glutamatergic synaptic function. (b) Gene structure and coordination of Ank1 loci associated with H3K4me3 depicted in Fig. 3c. (c) Whisker plot showing verification of changes in histone H3Me3K4 levels associated with gene loci identified in the ChIP-seq analysis by ChIP-PCR in independent samples from subjects treated with nicotine from birth to 21 days (postnatal-only) and evaluated at 3 months of age: F(1,8)= 11.02for Eif4a, p= 0.01054575; F(1,8)= 6.028 for Izumo1, p= 0.03961426; F(1,8)= 1.406 for Gpr19, p= 0.26974334; F(1,8)= 21.7 for Litaf, p= 0.00162698; F(1,8)= 15.839 for kcnq1, p= 0.00406270; F(1,8)= 19.147 for Lage3, p= 0.00236227; F(1,8)=17.512 for Fbxw4, p= 0.00305973; F(1,8)= 16.594 for Fgf12, p= 0.00356573; F(1,8)= 77.18 for Sepsecs, p= 0.00002212; F(1,8)= 9.979 for Rin2, p= 0.01341607; F(1,8)= 64.634 for Rabgap1l, p= 0.00004215; F(1,8)= 81.61 for Ano2, p= 0.00001803; F(1,8)= 17.505 for Apool, p= 0.00306323; F(1,8)= 99.602for Lipc, p= 0.00000862; F(1,8)= 45.502 for Cdk5rap2, p= 0.00014572; F(1,8)= 565.869 for Ing4, p= 0.00000001; F(1,8)= 118.256 for Ank3, p= 0.00000452; F(1,8)= 43.276 for Ntm, p= 0.00017324; F(1,8)= 487.52 for Zfp658, p= 0.00000002; F(1,8)= 8.77 for Ybx3, p= 0.01810693; F(1,7)= 41.57 for Sorcs1, p= 0.00019884; F(1,8)=153.564 for Lars2, p= 0.00000168; F(1,8)= 50.843 for Ank1, p= 0.00009898; F(1,8)= 242.093 for Acacb, p= 0.00000029; F(1,8)= 223.283 for Mdga2, p= 0.00000040; F(1,8)= 110.084 for Chl1, p= 0.00000592; F(1,8)= 23.981 for Auts2, p= 0.00119824; F(1,8)= 0.483 for Mbnl1, p= 0.50674655; F(1,8)=10.846 for Cpeb1, p= 0.01096747; F(1,8)= 15.121 for Zfp65, p= 0.00461852; F(1,8)= 5.928 for Chd9, p= 0.04089817; F(1,8)= 24.034 for Syt4, p= 0.00119008; F(1,8)=7.836 for Sp110, p= 0.02322340; F(1,8)= 51.276 for Sorbs2, p= 0.00009607; F(1,8)= 24.889 for Slc35a2, p= 0.00106755; F(1,8)= 19.501 for Mef2c, p= 0.00223843 (*p <0.05 with LSD test for multiple comparisons). Each replicate was a pool of 2-4 brain samples and 5 replicates were used for each condition (Sac: n = 5 pools from 14 animals; Nic: n = 5 pools from 12 animals). (d) Ash2l and Mef2c binding sites overlap with sites of H3K4me3 enrichment. Among these, GO analysis of 108 genomic sites identified as differentially enriched following nicotine exposure reveals that overlapped genomic sites are associated with synapse related functions.

Supplementary Figure 4 Regulation of Mef2c locus by nicotine treatment in vivo.

(a) Mef2c mRNA levels were significantly elevated at 21 days of age, immediately after nicotine exposure was completed F(1,8)=19.237, p=0.00232999. 5 Biological replicates per each condition from pooled female animals; Nic = 11 Sac = 15. (b) Histone H3 acetylation associated with the Mef2c locus was significantly increased as a result of nicotine exposure during development F(1,8)=118.802, p=0.00000445. 5 Biological replicates per each condition from pooled female animals; Nic = 12 Sac = 14. (c) Nicotine exposure during development significantly increased the level of H3K4me3 associated with the Mef2c locus (F(5,24)=10.403, p=0.000021) with Tukey's multiple comparison test. Frontal sac vs Frontal nic, p=0.001277; Parietal sac vs Parietal nic, p=0.005846; Occipital sac vs Occipital nic, p=0.011952. 5 Biological replicates per each condition from pooled female animals; Nic = 12 Sac = 12. *p < 0.05, *** p <0.01 with Sidak’s test.

Supplementary Figure 5 Evaluation of shRNA-mediated knock down of Ash2l and Mef2c protein levels in neural progenitor cells.

a) shRNA targeting Ash2l. b) shRNA targeting Mef2c. Original Western blots presented in supplementary Figure 7.

Supplementary Figure 6 Spread following in utero electroporation.

Example of the extent of shRNA spread and of GFP expression in a layer 6 cortical pyramidal neuron following in utero electroporation of shRNAs.

Supplementary Figure 7 Original images of representative western blot images in Figure 4 and Supplementary Figure 5.

(a-d) indicate uncropped LICOR machine scanned gel image with annotation. (e) Scanned film image of Figure 4 immunopreciptiation experiment. (f-g) Nicotine induced Wdr5 and Rbbp5 expression blot: original scanned image from LICOR machine. (i-j) Scanned images from LICOR machine for shRNA knockdown efficiency experiment presented in supplementary Figure 5.

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Jung, Y., Hsieh, L., Lee, A. et al. An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior. Nat Neurosci 19, 905–914 (2016).

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