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The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain

Nature Genetics volume 49, pages 1239–1250 (2017)Cite this article

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Abstract

We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Setdb1 (also known as Kmt1e; encodes a histone H3 lysine 9 methyltransferase), including a large topologically associated 1.2-Mb domain conserved in humans and mice that encompasses >70 genes at the clustered protocadherin locus (hereafter referred to as cPcdh). The cPcdh topologically associated domain (TADcPcdh) in neurons from mutant mice showed abnormal accumulation of the transcriptional regulator and three-dimensional (3D) genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression. Genes encoding stochastically expressed protocadherins were transcribed by increased numbers of cortical neurons, indicating relaxation of single-cell constraint. SETDB1-dependent loop formations bypassed 0.2–1 Mb of linear genome and radiated from the TADcPcdh fringes toward cis-regulatory sequences within the cPcdh locus, counterbalanced shorter-range facilitative promoter–enhancer contacts and carried loop-bound polymorphisms that were associated with genetic risk for schizophrenia. We show that the SETDB1 repressor complex, which involves multiple KRAB zinc finger proteins, shields neuronal genomes from excess CTCF binding and is critically required for structural maintenance of TADcPcdh.

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Figure 1: 3D genomes in Setdb1-deficient cortical neurons.
Figure 2: Histone modification and CTCF landscapes in Setdb1-deficient neuronal nuclei.
Figure 3: DNA methylation profiling at the cPcdh locus.
Figure 4: Transcriptional dysregulation at the cPcdh locus.
Figure 5: Epigenomic editing at the cPcdh locus.
Figure 6: Regulatory mechanisms at human and mouse TADcPcdh.

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Acknowledgements

We thank J. Gonzalez-Maeso (Virginia Commonwealth University) for kindly providing the Camk2a promoter plasmid. The work was supported by US National Institutes of Health (NIH) grants R01MH106056 (S.A.), P50MH096890 (E.J.N.), R01MH101454 (K.J.B.), NIA U01P50AG005138-30-1 (K.J.B.), U01AG046170 (K.J.B.), R01AG050986 (P. Roussos), R01MH109677, (P. Roussos) and R01NS091574 (A.S.), NIH training grant T32-AG049688 (S.C.) and NIH fellowship award 1F30MH113330 (P. Rajarajan). Additional support was provided by a Grant-in-Aid for AMED-CREST, AMED, Japan (T.Y.), the Japan–US Brain Research Cooperation Program (T.Y.), the Veterans Affairs Merit grant BX002395 (P. Roussos), the Brain and Behavior Research Foundation (Y.J. and P. Roussos), the Alzheimer's Association (P. Roussos), the New York Stem Cell Foundation (K.J.B.) and the Brain Research Foundation (S.A.).

Author information

Author notes

  1. Brigham J Hartley

    Present address: VL39 Inc., Cambridge, Massachusetts, USA

  2. Yan Jiang and Yong-Hwee Eddie Loh: These authors contributed equally to this work.

Authors and Affiliations

  1. Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Yan Jiang, Prashanth Rajarajan, Bibi S Kassim, Behnam Javidfar, Brigham J Hartley, Lisa Kleofas, Royce B Park, Seok-Man Ho, Sandhya Chandrasekaran, Cyril J Peter, Brian M Safaie, Hirofumi Morishita, Panos Roussos, Kristen J Brennand & Schahram Akbarian

  2. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Yong-Hwee Eddie Loh, Benoit Labonte, Brianna R Ramirez, Julia T C W, Eric J Nestler, Anne Schaefer & Li Shen

  3. Kokoro-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan

    Teruyoshi Hirayama & Takeshi Yagi

  4. New York Genome Center, New York, New York, USA

    Will Liao

  5. Department of Pathology and Cell Biology, Institute for Cancer Genetics, Columbia University, New York, New York, USA

    Catherine Do & Benjamin Tycko

  6. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA

    Catherine Do & Benjamin Tycko

  7. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Panos Roussos

  8. Mental Illness Research, Education and Clinical Center, James J. Peters Virginia Medical Center, New York, New York, USA

    Panos Roussos

Authors
  1. Yan Jiang
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  2. Yong-Hwee Eddie Loh
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Contributions

Y.J., P. Rajarajan, T.H., B.S.K., B.J.H., S.-M.H., B.J., L.K., R.B.P., S.C., C.D., C.J.P., J.T.C.W. and B.M.S. performed experiments; Y.J. and S.A. conceived and designed experiments; Y.J. performed statistical analyses; Y.-H.E.L., P. Rajarajan, W.L., P. Roussos and L.S. performed bioinformatics and genomic analyses; A.S., B.R.R. (G9a and GLP transcriptome data), B.L. and E.J.N. (mouse stress model and transcriptome data) contributed materials; B.T. supervised the DNA methylation analysis; H.M., K.J.B., T.Y., L.S. and S.A. supervised the research; Y.J., Y.-H.E.L., B.T., L.S. and S.A. wrote the paper with contributions from the other co-authors.

Corresponding author

Correspondence to Schahram Akbarian.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–19 and Supplementary Note (PDF 37458 kb)

Supplementary Table 1

Genome-wide epigenetic profiling of H3K9me3 in conditional CKCre+, Setdb1(2lox/2lox) mutant cortical neurons as compared to CK-Cre-, Setdb1(2lox/2lox) controls. N=3mice/genotype (2female, 1male). Adjusted P1.5. Mouse genome build mm10. (XLSX 184 kb)

Supplementary Table 2

Genome-wide epigenetic profiling of H3K27ac in conditional CKCre+, Setdb1(2lox/2lox) mutant cortical neurons as compared to CK-Cre-, Setdb1(2lox/2lox) controls. N=3 mice/genotype (all males). Adjusted P < 0.05. FC > 2. Mouse genome build mm10. (XLSX 108 kb)

Supplementary Table 3

Genome-wide epigenetic profiling of H3K9me3 in cortical nonneuronal (NeuN-) nuclei from conditional CK-Cre+, Setdb1(2lox/2lox) mutant, as compared to CK-Cre-, Setdb1(2lox/2lox) controls. N=3mice/genotype (2female, 1male). Adjusted P < 0.05 and FC > 1.5. Mouse genome build mm10. (XLSX 32 kb)

Supplementary Table 4

Genome-wide epigenetic profiling of H3K27ac in cortical nonneuronal (NeuN-) nuclei from conditional CK-Cre+, Setdb1(2lox/2lox) mutant, as compared to CK-Cre-, Setdb1(2lox/2lox) controls. N=3mice/genotype (2female, 1male). Adjusted P < 0.05 and FC > 2. Mouse genome build mm10. (XLSX 10 kb)

Supplementary Table 5

Homer motif search for genomic sequence with significant downregulated H3K9me3 hits in conditional CK-Cre+, Setdb1(2lox/2lox) mutant cortical neurons as compared to CK-Cre-, Setdb1(2lox/2lox) controls. Q-value < 0.05. CTCF motifs highlighted in yellow. (XLSX 10 kb)

Supplementary Table 6

Homer motif enrichment for genomic sequence with Setdb1 occupancy in mouse embryonic stem cell (Yuan P et al. 2009, Genes & Development). CTCF motifs are highlighted in yellow. (XLSX 15 kb)

Supplementary Table 7

Homer motif enrichment for genomic sequence with Setdb1 occupancy in CD19+ B cells (Pasquarella A. et al., 2016 Development). CTCF motifs are highlighted in yellow. (XLSX 26 kb)

Supplementary Table 8

Genome-wide epigenetic profiling of CTCF in conditional CK-Cre+, Setdb1(2lox/2lox) mutant cortical neurons as compared to CK-Cre-, Setdb1(2lox/2lox) controls. N=4 mice/genotype (3 female, 1 male). Adjusted P < 0.05. FC > 2. Mouse genome build mm10. (XLSX 282 kb)

Supplementary Table 9

Homer motif enrichment for genomic sequence with significantly up-regulated CTCF hits in CK-Cre+, Setdb1(2lox/2lox) mutant cortical neurons as compared to CK-Cre-, Setdb1(2lox/2lox) control cortical neurons. CTCF motifs are highlighted in yellow. (XLSX 17 kb)

Supplementary Table 10

Homer motif enrichment for genomic sequence with de novo CTCF peaks in CK-Cre+, Setdb1(2lox/2lox) mutant cortical neurons. CTCF motifs are highlighted in yellow (XLSX 21 kb)

Supplementary Table 11

Genome-wide comparison of CTCF and H3K9me3 alterations (DiffReps) in NeuN+ (adult cortex) of conditional CK-Cre+, Setdb1(2lox/2lox) mutant, as compared to CK-Cre-, Setdb1(2lox/2lox) controls. (XLSX 13 kb)

Supplementary Table 12

DNA methylation percentage of all amplicons at cPcdh sequences using neuronal and non-neuronal nuclei in cortex, striatum and cerebellum from CK-Cre+, Setdb1(2lox/2lox) mutant, as compared to CK-Cre-, Setdb1(2lox/2lox) controls. N=3-5mice/group. Mouse genome build mm10. (XLSX 39 kb)

Supplementary Table 13

Summary statistics DNA methylation at cis-regulatory cPcdh sequences (K = knock-out, W = wildtype, C=cerebral cortex, S=striatum, CB=Cerebellum, P= positive (NeuN immunoreactive), N=negative (non-NeuN). (XLSX 20 kb)

Supplementary Table 14

Differential transcriptome in conditional CK-Cre+, Setdb1(2lox/2lox) mutant prefrontal cortex as compared to CK-Cre-, Setdb1(2lox/2lox) controls. N=2mice/genotype (all female), adjusted P< 0.05. Mouse genome build mm10. (XLSX 47 kb)

Supplementary Table 15

Transgenic rescue of clustered Protocadherins. Mean±S.E.M. summarizing RNA quantification from Pcdh α, β, and γ clusters in prefrontal cortex of adult WT, TG, KO and RC mice (N=6/group), *P (XLSX 18 kb)

Supplementary Table 16

primer list (XLSX 20 kb)

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Jiang, Y., Loh, YH., Rajarajan, P. et al. The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nat Genet 49, 1239–1250 (2017). https://doi.org/10.1038/ng.3906

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