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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.

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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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