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Neurobiological functions of transcriptional enhancers

Abstract

Transcriptional enhancers are regulatory DNA elements that underlie the specificity and dynamic patterns of gene expression. Over the past decade, large-scale functional genomics projects have driven transformative progress in our understanding of enhancers. These data have relevance for identifying mechanisms of gene regulation in the CNS, elucidating the function of non-coding regulatory sequences in neurobiology and linking sequence variation within enhancers to genetic risk for neurological and psychiatric disorders. However, the sheer volume and complexity of genomic data presents a challenge to interpreting enhancer function in normal and pathogenic neurobiological processes. Here, to advance the application of genome-scale enhancer data, we offer a primer on current models of enhancer function in the CNS, we review how enhancers regulate gene expression across the neuronal lifespan, and we suggest how emerging findings regarding the role of non-coding sequence variation offer opportunities for understanding brain disorders and developing new technologies for neuroscience.

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Fig. 1: Enhancer function is dependent on sequence and context.
Fig. 2: General models of CNS regulatory wiring.
Fig. 3: Enhancers across the neuronal lifespan.
Fig. 4: How disease-associated SNPs impact enhancer function.

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References

  1. Kellis, M. et al. Defining functional DNA elements in the human genome. Proc. Natl. Acad. Sci. USA 111, 6131–6138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

  3. Ecker, J. R. et al. The BRAIN Initiative Cell Census Consortium. The BRAIN Initiative Cell Census Consortium: lessons learned toward generating a comprehensive brain cell atlas. Neuron 96, 542–557 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. PsychENCODE Consortium. Revealing the brain’s molecular architecture. Science 362, 1262–1263 (2018).

  5. Banerji, J., Rusconi, S. & Schaffner, W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299–308 (1981).

    Article  CAS  PubMed  Google Scholar 

  6. Voss, S. D., Schlokat, U. & Gruss, P. The role of enhancers in the regulation of cell-type-specific transcriptional control. Trends Biochem. Sci. 11, 287–289 (1986).

    Article  CAS  Google Scholar 

  7. O’Kane, C. J. & Gehring, W. J. Detection in situ of genomic regulatory elements. Drosoph. Proc. Natl. Acad. Sci. USA 84, 9123–9127 (1987).

    Article  Google Scholar 

  8. Song, L. et al. Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Res. 21, 1757–1767 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cao, J. et al. Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361, 1380–1385 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cusanovich, D. A. et al. The cis-regulatory dynamics of embryonic development at single-cell resolution. Nature 555, 538–542 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cao, J. et al. Comprehensive single-cell transcriptional profiling of a multicellular organism. Science 357, 661–667 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang, J. et al. Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors. Genome Res. 22, 1798–1812 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Inukai, S., Kock, K. H. & Bulyk, M. L. Transcription factor-DNA binding: beyond binding site motifs. Curr. Opin. Genet. Dev. 43, 110–119 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hombach, D., Schwarz, J. M., Robinson, P. N., Schuelke, M. & Seelow, D. A systematic, large-scale comparison of transcription factor binding site models. BMC Genomics 17, 388 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Becker, P. B. & Workman, J. L. Nucleosome remodeling and epigenetics. Cold Spring Harb. Perspect. Biol. 5, a017905 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Thurman, R. E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Maurano, M. T. et al. Role of DNA methylation in modulating transcription factor occupancy. Cell Rep. 12, 1184–1195 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Zuo, Z., Roy, B., Chang, Y. K., Granas, D. & Stormo, G. D. Measuring quantitative effects of methylation on transcription factor-DNA binding affinity. Sci. Adv. 3, o1799 (2017).

    Article  CAS  Google Scholar 

  19. Lettice, L. A. et al. Enhancer-adoption as a mechanism of human developmental disease. Hum. Mutat. 32, 1492–1499 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Lupiáñez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Lupiáñez, D. G., Spielmann, M. & Mundlos, S. Breaking TADs: how alterations of chromatin domains result in disease. Trends Genet. 32, 225–237 (2016).

    Article  PubMed  CAS  Google Scholar 

  22. Bird, A. P. & Wolffe, A. P. Methylation-induced repression-belts, braces, and chromatin. Cell 99, 451–454 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Nord, A. S. Learning about mammalian gene regulation from functional enhancer assays in the mouse. Genomics 106, 178–184 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Maricque, B. B., Chaudhari, H. G. & Cohen, B. A. A massively parallel reporter assay dissects the influence of chromatin structure on cis-regulatory activity. Nat. Biotechnol. 37, 90–95 (2018).

    Article  CAS  Google Scholar 

  25. Levine, M., Cattoglio, C. & Tjian, R. Looping back to leap forward: transcription enters a new era. Cell 157, 13–25 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kuras, L., Borggrefe, T. & Kornberg, R. D. Association of the Mediator complex with enhancers of active genes. Proc. Natl. Acad. Sci. USA 100, 13887–13891 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ren, G. et al. CTCF-mediated enhancer-promoter interaction is a critical regulator of cell-to-cell variation of gene expression. Mol. Cell 67, 1049–1058.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang, Y. et al. Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature 504, 306–310 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nolis, I. K. et al. Transcription factors mediate long-range enhancer-promoter interactions. Proc. Natl. Acad. Sci. USA 106, 20222–20227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Diao, Y. et al. A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat. Methods 14, 629–635 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Joo, J. Y., Schaukowitch, K., Farbiak, L., Kilaru, G. & Kim, T. K. Stimulus-specific combinatorial functionality of neuronal c-fos enhancers. Nat. Neurosci. 19, 75–83 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Mitchell, A. C. et al. Longitudinal assessment of neuronal 3D genomes in mouse prefrontal cortex. Nat. Commun. 7, 12743 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. van Arensbergen, J., van Steensel, B. & Bussemaker, H. J. In search of the determinants of enhancer-promoter interaction specificity. Trends Cell Biol. 24, 695–702 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Hnisz, D., Shrinivas, K., Young, R. A., Chakraborty, A. K. & Sharp, P. A. A phase separation model for transcriptional control. Cell 169, 13–23 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sigova, A. A. et al. Transcription factor trapping by RNA in gene regulatory elements. Science 350, 978–981 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen, H. et al. Dynamic interplay between enhancer-promoter topology and gene activity. Nat. Genet. 50, 1296–1303 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Bothma, J. P. et al. Dynamic regulation of Eve Stripe 2 expression reveals transcriptional bursts in living Drosophila embryos. Proc. Natl. Acad. Sci. USA 111, 10598–10603 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sutherland, H. & Bickmore, W. A. Transcription factories: gene expression in unions? Nat. Rev. Genet. 10, 457–466 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Dowen, J. M. et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell 159, 374–387 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Akbarian, S. et al. The PsychENCODE project. Nat. Neurosci. 18, 1707–1712 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Luo, C. et al. Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex. Science 357, 600–604 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Preissl, S. et al. Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nat. Neurosci. 21, 432–439 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lake, B. B. et al. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36, 70–80 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Wang, X. et al. Three-dimensional intact-tissue sequencing of single-cell transcriptional states. Science 361, eaat5691 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Kwasnieski, J. C., Fiore, C., Chaudhari, H. G. & Cohen, B. A. High-throughput functional testing of ENCODE segmentation predictions. Genome Res. 24, 1595–1602 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Inoue, F. & Ahituv, N. Decoding enhancers using massively parallel reporter assays. Genomics 106, 159–164 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Visel, A. et al. A high-resolution enhancer atlas of the developing telencephalon. Cell 152, 895–908 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mumbach, M. R. et al. HiChIP: efficient and sensitive analysis of protein-directed genome architecture. Nat. Methods 13, 919–922 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shen, S. Q. et al. Massively parallel cis-regulatory analysis in the mammalian central nervous system. Genome Res. 26, 238–255 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Grossman, S. R. et al. Positional specificity of different transcription factor classes within enhancers. Proc. Natl. Acad. Sci. USA 115, E7222–E7230 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Nguyen, T. A. et al. High-throughput functional comparison of promoter and enhancer activities. Genome Res. 26, 1023–1033 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dickel, D. E. et al. Ultraconserved enhancers are required for normal development. Cell 172, 491–499.e15 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xie, S., Duan, J., Li, B., Zhou, P. & Hon, G. C. Multiplexed engineering and analysis of combinatorial enhancer activity in single cells. Mol. Cell 66, 285–299.e5 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Canver, M. C. et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527, 192–197 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Huang, J. et al. Dissecting super-enhancer hierarchy based on chromatin interactions. Nat. Commun. 9, 943 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Chen, L. F., Zhou, A. S. & West, A. E. Transcribing the connectome: roles for transcription factors and chromatin regulators in activity-dependent synapse development. J. Neurophysiol. 118, 755–770 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Robison, A. J. & Nestler, E. J. Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. 12, 623–637 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yap, E. L. & Greenberg, M. E. Activity-regulated transcription: bridging the gap between neural activity and behavior. Neuron 100, 330–348 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Prescott, S. L. et al. Enhancer divergence and cis-regulatory evolution in the human and chimp neural crest. Cell 163, 68–83 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. de la Torre-Ubieta, L. et al. The dynamic landscape of open chromatin during human cortical neurogenesis. Cell 172, 289–304.e18 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Frank, C. L. et al. Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum. Nat. Neurosci. 18, 647–656 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rhee, H. S. et al. Expression of terminal effector genes in mammalian neurons is maintained by a dynamic relay of transient enhancers. Neuron 92, 1252–1265 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nord, A. S. et al. Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell 155, 1521–1531 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sandberg, M. et al. Transcriptional networks controlled by NKX2-1 in the development of forebrain GABAergic neurons. Neuron 91, 1260–1275 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cusanovich, D. A., Pavlovic, B., Pritchard, J. K. & Gilad, Y. The functional consequences of variation in transcription factor binding. PLoS Genet. 10, e1004226 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49, 825–837 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Spicuglia, S. & Vanhille, L. Chromatin signatures of active enhancers. Nucleus 3, 126–131 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl. Acad. Sci. USA 107, 21931–21936 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Russ, B. E. et al. Regulation of H3K4me3 at transcriptional enhancers characterizes acquisition of virus-specific CD8+ T cell-lineage-specific function. Cell Rep. 21, 3624–3636 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Whyte, W. A. et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482, 221–225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lister, R. et al. Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Zhu, J. et al. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell 152, 642–654 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Preger-Ben Noon, E. et al. Comprehensive analysis of a cis-regulatory region reveals pleiotropy in enhancer function. Cell Rep. 22, 3021–3031 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. Wenger, A. M. et al. The enhancer landscape during early neocortical development reveals patterns of dense regulation and co-option. PLoS Genet. 9, e1003728 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bakken, T. E. et al. A comprehensive transcriptional map of primate brain development. Nature 535, 367–375 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Roberts, A. C. et al. Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63, 342–356 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sheng, M., Cummings, J., Roldan, L. A., Jan, Y. N. & Jan, L. Y. Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368, 144–147 (1994).

    Article  CAS  PubMed  Google Scholar 

  85. Thakurela, S., Sahu, S. K., Garding, A. & Tiwari, V. K. Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity. Genome Res. 25, 1309–1324 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Daum, J. M. et al. The formation of the light-sensing compartment of cone photoreceptors coincides with a transcriptional switch. eLife 6, e31437 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Rouaux, C. & Arlotta, P. Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo. Nat. Cell Biol. 15, 214–221 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Holtzman, L. & Gersbach, C. A. Editing the epigenome: reshaping the genomic landscape. Annu. Rev. Genomics Hum. Genet. 19, 43–71 (2018).

    Article  CAS  PubMed  Google Scholar 

  89. Deneris, E. S. & Hobert, O. Maintenance of postmitotic neuronal cell identity. Nat. Neurosci. 17, 899–907 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lyons, M. R. & West, A. E. Mechanisms of specificity in neuronal activity-regulated gene transcription. Prog. Neurobiol. 94, 259–295 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gray, J. M. et al. Genomic views of transcriptional enhancers: essential determinants of cellular identity and activity-dependent responses in the CNS. J. Neurosci. 35, 13819–13826 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Whitney, O. et al. Core and region-enriched networks of behaviorally regulated genes and the singing genome. Science 346, 1256780 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Mardinly, A. R. et al. Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 531, 371–375 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hrvatin, S. et al. Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. Nat. Neurosci. 21, 120–129 (2018).

    Article  CAS  PubMed  Google Scholar 

  95. Spiegel, I. et al. Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs. Cell 157, 1216–1229 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Madabhushi, R. & Kim, T. K. Emerging themes in neuronal activity-dependent gene expression. Mol. Cell. Neurosci. 87, 27–34 (2018).

    Article  CAS  PubMed  Google Scholar 

  97. Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Schaukowitch, K. et al. Enhancer RNA facilitates NELF release from immediate early genes. Mol. Cell 56, 29–42 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bose, D. A. et al. RNA binding to CBP stimulates histone acetylation and transcription. Cell 168, 135–149.e22 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Malik, A. N. et al. Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nat. Neurosci. 17, 1330–1339 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chen, L. F. et al. Enhancer histone acetylation modulates transcriptional bursting dynamics of neuronal activity-inducible genes. Cell Rep. 26, 1174–1188.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zippo, A. et al. Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell 138, 1122–1136 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Yamada, T. et al. Sensory experience remodels genome architecture in neural circuit to drive motor learning. Nature 569, 708–713 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Walczak, A. et al. Novel higher-order epigenetic regulation of the Bdnf gene upon seizures. J. Neurosci. 33, 2507–2511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Su, Y. et al. Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat. Neurosci. 20, 476–483 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Vierbuchen, T. et al. AP-1 transcription factors and the BAF complex mediate signal-dependent enhancer selection. Mol. Cell 68, 1067–1082.e12 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Jeong, Y. et al. Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat. Genet. 40, 1348–1353 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Vacic, V. et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471, 499–503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Blumenthal, I. et al. Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families. Am. J. Hum. Genet. 94, 870–883 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Collins, F. S. & Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 372, 793–795 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yuen, C. & K., R. et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat. Neurosci. 20, 602–611 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  112. Werling, D. M. et al. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. Nat. Genet. 50, 727–736 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bryois, J. et al. Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nat. Commun. 9, 3121 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Turner, T. N. et al. Genomic patterns of de novo mutation in simplex autism. Cell 171, 710–722.e12 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. An, J. Y. et al. Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science 362, eaat6576 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Doan, R. N. et al. Mutations in human accelerated regions disrupt cognition and social behavior. Cell 167, 341–354.e12 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Short, P. J. et al. De novo mutations in regulatory elements in neurodevelopmental disorders. Nature 555, 611–616 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

    Article  PubMed Central  CAS  Google Scholar 

  119. Yu, D. et al. Interrogating the genetic determinants of Tourette’s syndrome and other tic disorders through genome-wide association studies. Am. J. Psychiatry 176, 217–227 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Grove, J. et al. Identification of common genetic risk variants for autism spectrum disorder. Nat. Genet. 51, 431–444 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Howard, D. M. et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat. Neurosci. 22, 343–352 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Demontis, D. et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat. Genet. 51, 63–75 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Roussos, P. et al. A role for noncoding variation in schizophrenia. Cell Rep. 9, 1417–1429 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Gusev, A. et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Won, H. et al. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538, 523–527 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Rajarajan, P. et al. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science 362, eaat4311 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Visscher, P. M. et al. 10 years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet. 101, 5–22 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Klengel, T. et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat. Neurosci. 16, 33–41 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Gallagher, M. D. et al. A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression. Am. J. Hum. Genet. 101, 643–663 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Dimidschstein, J. et al. A viral strategy for targeting and manipulating interneurons across vertebrate species. Nat. Neurosci. 19, 1743–1749 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. McLean, C. Y. et al. Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature 471, 216–219 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lewin, H. A. et al. Earth BioGenome Project: sequencing life for the future of life. Proc. Natl. Acad. Sci. USA 115, 4325–4333 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Meyer, M. et al. A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014).

    Article  PubMed  CAS  Google Scholar 

  135. McCoy, R. C., Wakefield, J. & Akey, J. M. Impacts of Neanderthal-introgressed sequences on the landscape of human gene expression. Cell 168, 916–927.e12 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 1000 Genomes Project Consortium, Auton, A. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article  CAS  Google Scholar 

  137. Wang, D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 362, eaat8464 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Dobbyn, A. et al. Landscape of conditional eQTL in dorsolateral prefrontal cortex and co-localization with schizophrenia GWAS. Am. J. Hum. Genet. 102, 1169–1184 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Matharu, N. et al. CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science 363, eaau0629 (2019).

    Article  CAS  PubMed  Google Scholar 

  140. Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet. 51, 404–413 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Amiri, A. et al. Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science 362, eaat6720 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Berson, A., Nativio, R., Berger, S. L. & Bonini, N. M. Epigenetic regulation in neurodegenerative diseases. Trends Neurosci. 41, 587–598 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Klein, H. U. et al. Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains. Nat. Neurosci. 22, 37–46 (2019).

    Article  CAS  PubMed  Google Scholar 

  144. Nativio, R. et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat. Neurosci. 21, 497–505 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by NIH R35GM119831 (A.S.N.) and R01NS098804 (A.E.W.).

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A.S.N. and A.E.W. conceived of the review, researched the literature, wrote the manuscript and revised the manuscript.

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Correspondence to Alex S. Nord or Anne E. West.

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Peer review information Nature Neuroscience thanks Erica Korb, Ian Maze, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Nord, A.S., West, A.E. Neurobiological functions of transcriptional enhancers. Nat Neurosci 23, 5–14 (2020). https://doi.org/10.1038/s41593-019-0538-5

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