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Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells

Nature Genetics volume 51, pages 1691–1701 (2019)Cite this article

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Abstract

In the mammalian genome, the clustered protocadherin (cPCDH) locus provides a paradigm for stochastic gene expression with the potential to generate a unique cPCDH combination in every neuron. Here we report a chromatin-based mechanism that emerges during the transition from the naive to the primed states of cell pluripotency and reduces, by orders of magnitude, the combinatorial potential in the human cPCDH locus. This mechanism selectively increases the frequency of stochastic selection of a small subset of cPCDH genes after neuronal differentiation in monolayers, 10-month-old cortical organoids and engrafted cells in the spinal cords of rats. Signs of these frequent selections can be observed in the brain throughout fetal development and disappear after birth, except in conditions of delayed maturation such as Down’s syndrome. We therefore propose that a pattern of limited cPCDH-gene expression diversity is maintained while human neurons still retain fetal-like levels of maturation.

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Fig. 1: Non-uniform probability of cPCDH-gene selection in hiPSC-derived neurons.
Fig. 2: Chromatin in hiPSCs mirrors expression in hiPSC-derived neurons across the cPCDH locus.
Fig. 3: In vitro-generated neurons inherit cPCDH-locus features from non-neuronal cells.
Fig. 4: Differences in cPCDH-locus chromatin organization between naive and primed cells.
Fig. 5: Signs of hESC-guided cPCDH-gene signatures are remarkably stable in vitro and in vivo.
Fig. 6: Two distinct types of cPCDH diversity distinguish fetal and adult brain tissues.

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Data availability

The sequencing datasets generated in this study have been deposited in GEO under accession number GSE106872.

References

  1. Gul, I. S., Hulpiau, P., Saeys, Y. & van Roy, F. Evolution and diversity of cadherins and catenins. Exp. Cell Res. 358, 3–9 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Hirayama, T. & Yagi, T. Regulation of clustered protocadherin genes in individual neurons. Semin. Cell Dev. Biol. 69, 122–130 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Peek, S. L., Mah, K. M. & Weiner, J. A. Regulation of neural circuit formation by protocadherins. Cell. Mol. Life Sci. 74, 4133–4157 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mountoufaris, G., Canzio, D., Nwakeze, C. L., Chen, W. V. & Maniatis, T. Writing, reading, and translating the clustered protocadherin cell surface recognition code for neural circuit assembly. Annu. Rev. Cell Dev. Biol. 34, 471–493 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Rubinstein, R., Goodman, K. M., Maniatis, T., Shapiro, L. & Honig, B. Structural origins of clustered protocadherin-mediated neuronal barcoding. Semin. Cell Dev. Biol. 69, 140–150 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Garrett, A. M., Schreiner, D., Lobas, M. A. & Weiner, J. A. γ-Protocadherins control cortical dendrite arborization by regulating the activity of a FAK/PKC/MARCKS signaling pathway. Neuron 74, 269–276 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kostadinov, D. & Sanes, J. R. Protocadherin-dependent dendritic self-avoidance regulates neural connectivity and circuit function. eLife 4, e08964 (2015).

  8. Lefebvre, J. L., Kostadinov, D., Chen, W. V., Maniatis, T. & Sanes, J. R. Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature 488, 517–521 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Molumby, M. J., Keeler, A. B. & Weiner, J. A. Homophilic protocadherin cell–cell interactions promote dendrite complexity. Cell Rep. 15, 1037–1050 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mountoufaris, G. et al. Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly. Science 356, 411–414 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang, X., Su, H. & Bradley, A. Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model. Genes Dev. 16, 1890–1905 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tasic, B. et al. Promoter choice determines splice site selection in protocadherin α and γ pre-mRNA splicing. Mol. Cell 10, 21–33 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Chen, W. V. & Maniatis, T. Clustered protocadherins. Development 140, 3297–3302 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guo, Y. et al. CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice. Proc. Natl Acad. Sci. USA 109, 21081–21086 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Guo, Y. et al. CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell 162, 900–910 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kehayova, P., Monahan, K., Chen, W. & Maniatis, T. Regulatory elements required for the activation and repression of the protocadherin-α gene cluster. Proc. Natl Acad. Sci. USA 108, 17195–17200 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Monahan, K. et al. Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of protocadherin-α gene expression. Proc. Natl Acad. Sci. USA 109, 9125–9130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ribich, S., Tasic, B. & Maniatis, T. Identification of long-range regulatory elements in the protocadherin-α gene cluster. Proc. Natl Acad. Sci. USA 103, 19719–19724 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jiang, Y. et al. The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nat. Genet. 49, 1239–1250 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. El Hajj, N., Dittrich, M. & Haaf, T. Epigenetic dysregulation of protocadherins in human disease. Semin. Cell Dev. Biol. 69, 172–182 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Woodruff, G. et al. Defective transcytosis of APP and lipoproteins in human iPSC-derived neurons with familial Alzheimer’s disease mutations. Cell Rep. 17, 759–773 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Woodruff, G. et al. The presenilin-1 ΔE9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep. 5, 974–985 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mertens, J. et al. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 17, 705–718 (2015).

  25. Cacchiarelli, D. et al. Integrative analyses of human reprogramming reveal dynamic nature of induced pluripotency. Cell 162, 412–424 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kilens, S. et al. Parallel derivation of isogenic human primed and naive induced pluripotent stem cells. Nat. Commun. 9, 360 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. O’Leary, T. et al. Tracking the progression of the human inner cell mass during embryonic stem cell derivation. Nat. Biotechnol. 30, 278–282 (2012).

    Article  PubMed  CAS  Google Scholar 

  28. Warrier, S. et al. Transcriptional landscape changes during human embryonic stem cell derivation. Mol. Hum. Reprod. 24, 543–555 (2018).

    CAS  PubMed  Google Scholar 

  29. Theunissen, T. W. et al. Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell 15, 471–487 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ji, X. et al. 3D chromosome regulatory landscape of human pluripotent cells. Cell Stem Cell 18, 262–275 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Theunissen, T. W. & Jaenisch, R. Mechanisms of gene regulation in human embryos and pluripotent stem cells. Development 144, 4496–4509 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yagi, T. Molecular codes for neuronal individuality and cell assembly in the brain. Front. Mol. Neurosci. 5, 45 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wada, T., Wallerich, S. & Becskei, A. Stochastic gene choice during cellular differentiation. Cell Rep. 24, 3503–3512 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Trujillo, C. A. et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 25, 558–569 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Brown, J. P. et al. Transient expression of doublecortin during adult neurogenesis. J. Comp. Neurol. 467, 1–10 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Stiles, J. & Jernigan, T. L. The basics of brain development. Neuropsychol. Rev. 20, 327–348 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Frank, M. et al. Differential expression of individual gamma-protocadherins during mouse brain development. Mol. Cell. Neurosci. 29, 603–616 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Li, Y. et al. Synaptic and nonsynaptic localization of protocadherin-γC5 in the rat brain. J. Comp. Neurol. 518, 3439–3463 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zou, C., Huang, W., Ying, G. & Wu, Q. Sequence analysis and expression mapping of the rat clustered protocadherin gene repertoires. Neuroscience 144, 579–603 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Bohaciakova, D. et al. A scalable solution for isolating human multipotent clinical-grade neural stem cells from ES precursors. Stem Cell Res. Ther. 10, 83 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Toyoda, S. et al. Developmental epigenetic modification regulates stochastic expression of clustered protocadherin genes, generating single neuron diversity. Neuron 82, 94–108 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Miller, J. A. et al. Transcriptional landscape of the prenatal human brain. Nature 508, 199–206 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Juhasova, J. et al. Time course of spinal doublecortin expression in developing rat and porcine spinal cord: implication in in vivo neural precursor grafting studies. Cell. Mol. Neurobiol. 35, 57–70 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. El Hajj, N. et al. Epigenetic dysregulation in the developing Down syndrome cortex. Epigenetics 11, 563–578 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Horvath, S. et al. Accelerated epigenetic aging in Down syndrome. Aging Cell 14, 491–495 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Esumi, S. et al. Monoallelic yet combinatorial expression of variable exons of the protocadherin-α gene cluster in single neurons. Nat. Genet. 37, 171–176 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Smith, A. Formative pluripotency: the executive phase in a developmental continuum. Development 144, 365–373 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Takashima, Y. et al. Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell 158, 1254–1269 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Borgel, J. et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nat. Genet. 42, 1093–1100 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Hasegawa, S. et al. The protocadherin-α family is involved in axonal coalescence of olfactory sensory neurons into glomeruli of the olfactory bulb in mouse. Mol. Cell. Neurosci. 38, 66–79 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Hasegawa, S. et al. Distinct and cooperative functions for the protocadherin-α, -β and -γ clusters in neuronal survival and axon targeting. Front. Mol. Neurosci. 9, 155 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Hasegawa, S. et al. Clustered protocadherins are required for building functional neural circuits. Front. Mol. Neurosci. 10, 114 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Katori, S. et al. Protocadherin-α family is required for serotonergic projections to appropriately innervate target brain areas. J. Neurosci. 29, 9137–9147 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Prasad, T. & Weiner, J. A. Direct and indirect regulation of spinal cord Ia afferent terminal formation by the γ-protocadherins. Front. Mol. Neurosci. 4, 54 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Suo, L., Lu, H., Ying, G., Capecchi, M. R. & Wu, Q. Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase. J. Mol. Cell Biol. 4, 362–376 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Chen, W. V. et al. Pcdhαc2 is required for axonal tiling and assembly of serotonergic circuitries in mice. Science 356, 406–411 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yamagishi, T. et al. Molecular diversity of clustered protocadherin-α required for sensory integration and short-term memory in mice. Sci. Rep. 8, 9616 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Young, J. E. et al. Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell 16, 373–385 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cowan, C. A. et al. Derivation of embryonic stem-cell lines from human blastocysts. N. Engl. J. Med. 350, 1353–1356 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Ying, Q.-L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J. C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Guo, G. et al. Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136, 1063–1069 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yuan, S. H. et al. Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells. PLoS ONE 6, e17540 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Shi, Y., Kirwan, P. & Livesey, F. J. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat. Protoc. 7, 1836–1846 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Shi, Y., Kirwan, P., Smith, J., Robinson, H. P. C. & Livesey, F. J. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 15, 477–486 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Fong, L. K. et al. Full-length amyloid precursor protein regulates lipoprotein metabolism and amyloid-β clearance in human astrocytes. J. Biol. Chem. 293, 11341–11357 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Crook, J. M. et al. The generation of six clinical-grade human embryonic stem cell lines. Cell Stem Cell 1, 490–494 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Mann, D. L. et al. Origin of the HIV-susceptible human CD4+ cell line H9. AIDS Res. Hum. Retroviruses 5, 253–255 (1989).

    Article  CAS  PubMed  Google Scholar 

  70. Hefferan, M. P. et al. Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation. PLoS ONE 7, e42614 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kakinohana, O. et al. Region-specific cell grafting into cervical and lumbar spinal cord in rat: a qualitative and quantitative stereological study. Exp. Neurol. 190, 122–132 (2004).

    Article  PubMed  Google Scholar 

  72. Almenar-Queralt, A. et al. Presenilins regulate neurotrypsin gene expression and neurotrypsin-dependent agrin cleavage via cyclic AMP response element-binding protein (CREB) modulation. J. Biol. Chem. 288, 35222–35236 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Benner, C. et al. Decoding a signature-based model of transcription cofactor recruitment dictated by cardinal cis-regulatory elements in proximal promoter regions. PLoS Genet. 9, e1003906 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Johnson, W. E., Li, C. & Rabinovic, A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118–127 (2007).

    Article  PubMed  Google Scholar 

  76. Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank M. G. Rosenfeld and W. Dillmann for providing a nurturing research environment to perform this study, and the many colleagues who helped us to conduct or understand our research (in alphabetical order): A. Becskei, A. Gamliel, T. Haaf, A. Holder, K. Jepsen, E. Kothari, S. Linker, C. Marchetto, S. Marsala, J. Mertens, I. Narvaiza, F. Neri, D. Meluzzi, A. Muotri, P. Negraes, K. Ohgi, M. Parast, S. Sathe, D. Skowronska-Krawczyk, C. Trujillo, R. Tsunemoto, R. Van der Kant, G. Yeo; the team at the UCSD Human Embryonic Stem Cell Core Facility for reagents and technical assistance, and the ENCODE and BrainSpan Consortia for sharing data. Special thanks to H. Garcia Garcia in representation of the many deceased anonymous donors who altruistically donate their bodies for the advancement of science; these donors have made our work possible. Q.M. was supported by the postdoctoral fellowship from the American Cancer Society. C.A. was supported by the postdoctoral fellowship Sara Borrell. Study supported by the US Department of Defense (DoD) (AZ140064) to A.A.-Q., the Sanford Stem Cell Clinical Center (SANPORC) to M.M. and NIH/NIA (1RF1AG048083-01 and 5P50AG005131-34) to L.S.B.G. The Department of Medicine, School of Medicine (UCSD) supported I.G.-B.

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Authors and Affiliations

  1. Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA

    Angels Almenar-Queralt, Daria Merkurjev, Hong Sook Kim, Qi Ma, Catarina Allegue, Carlos Mackintosh & Ivan Garcia-Bassets

  2. Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA

    Angels Almenar-Queralt, Rodrigo S. Chaves, Andrew G. Chen, Bridget Kohlnhofer, Lauren K. Fong, Grace Woodruff, Martin Marsala & Lawrence S. B. Goldstein

  3. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA

    Angels Almenar-Queralt, Rodrigo S. Chaves, Andrew G. Chen, Bridget Kohlnhofer, Lauren K. Fong, Grace Woodruff & Lawrence S. B. Goldstein

  4. Department of Statistics, University of California, Los Angeles, Los Angeles, CA, USA

    Daria Merkurjev

  5. Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA

    Michael Navarro, Dasa Bohaciakova, Marian Hruska-Plochan, Takahiro Tadokoro & Martin Marsala

  6. Center for Research in Molecular Medicine and Chronic Diseases, Santiago de Compostela, Spain

    Catarina Allegue

  7. Salk Institute for Biological Studies, La Jolla, CA, USA

    Shawn P. Driscoll

  8. Department of Pathology and Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA, USA

    Jessica E. Young

  9. College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar

    Nady El Hajj

  10. Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany

    Nady El Hajj & Marcus Dittrich

  11. Department of Bioinformatics, Julius Maximilians University, Würzburg, Germany

    Marcus Dittrich

  12. Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA

    Lawrence S. B. Goldstein

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  1. Angels Almenar-Queralt
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Contributions

A.A.-Q. and I.G.-B. conceived and designed experiments. A.A.-Q., H.S.K., M.N., R.S.C., A.G.C., B.K., L.K.F., J.E.Y. and I.G.-B. performed experiments. D.M., Q.M., C.A., S.P.D., C.M., N.E.H, M.D. and I.G.B. performed computational analyses. G.W., D.B., M.H.-P. and T.T. generated essential reagents. A.A.-Q., M.M., L.S.B.G. and I.G.-B. supervised the research. A.A.-Q. and I.G.-B. wrote the manuscript.

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Correspondence to Angels Almenar-Queralt or Ivan Garcia-Bassets.

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M.M. is the scientific founder of Neurgain Technologies and has an equity interest in the company. In addition, M.M. serves as a consultant to Neurgain Technologies and receives compensation for these services. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

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Almenar-Queralt, A., Merkurjev, D., Kim, H.S. et al. Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells. Nat Genet 51, 1691–1701 (2019). https://doi.org/10.1038/s41588-019-0526-4

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