Single-cell epigenomic reconstruction of developmental trajectories in human neural organoid systems from pluripotency
Posted on: 4 January 2024 , updated on: 9 January 2024
Preprint posted on 13 September 2023
Article now published in Nature Neuroscience at http://dx.doi.org/10.1038/s41593-024-01652-0
An insight into the fascinating world of neurodevelopment: histone modifications put the brakes on stem cell potential during organogenesis.
Selected by Manuel Lessi
Categories: cell biology, developmental biology, genomics, neuroscience
Introduction
Development of tissues and organs requires tightly controlled molecular signaling that guides undifferentiated cells to acquire specific restricted fates. This is especially true for the brain, whose intricate developmental unfolding is dependent on distinct cell types being produced in a timely and regulated manner starting from the pluripotent progenitor cells in the ventricular zone (1). Any deviations from such developmental trajectories can lead to developmental abnormalities like cell type imbalances, incorrect neuron wiring, and ultimately neurodevelopmental disorders. It is therefore extremely important to underpin the genetic, epigenetic, as well as environmental factors that drive stem cell fate restrictions as they differentiate into mature brain cell types. Despite the importance of studying such processes, it is difficult to do because it requires access to fetal brain samples which are scarce and come with ethical concerns (2). In the last decade, pluripotent stem cells-derived brain organoids have become an unparalleled tool for investigating physiological trajectories of human neurodevelopment and its pathological alterations in vitro, as they recapitulate early growth of the fetal brain in a dish (3–7).
Figure 1: Brain organoids are a valuable tool that recapitulates neurodevelopment in a dish as they retain the main cell types, cytoarchitecture, and gene expression of the human fetal primary brain. Adapted from Yang Qian et al. 2022 (8).
Background of the Preprint
Histone modifications play a pivotal role in determining cellular differentiation in organ and tissue development, nevertheless the molecular mechanisms that explain such complex processes remain to be elucidated (9). Among the hundreds of epigenetic signatures that can be investigated, the most studied and best characterized are:
- H3K27me3: Marker of transcription repression during development,
- H3K27ac: Marker of active enhancer/promoter,
- H3K4me3: Marker of active or bivalent promoters of developmental genes.
Despite their known role in gene regulation, molecular and phenotypical effects linked to these epigenetic marks in specific cell lineages in the developing brain are still to be addressed. Significantly, recent advancements in single-cell omics profiling provide an unprecedented opportunity to delve into the molecular intricacies governing the physiological properties of biological systems.
In this preprint, the authors aimed to construct a comprehensive single-cell atlas encompassing gene expression and the three histone modifications (H3K27me3, H3K27ac, H3K4me3) during neurodevelopment by profiling brain organoids in a time course, from the early pluripotent state to comprehensive tissue maturation. This is instrumental in addressing restriction of developmental plasticity phenomena in pluripotent cells during differentiation.
Key findings
The authors were able to identify the main cell types generated during human brain development along with their histone marker modifications, unraveling molecular mechanisms by which the epigenome influences gene expression and instructs cellular plasticity.
The main findings can be summarized in a few key points:
- The expression of brain region-specific transcription factors is recapitulated in brain organoids. The expression of these transcription factors is repressed by H3K27me3 in other brain regions.
- Histone modifications play a pivotal role in neurodevelopment, influencing the expression of over 60% of all profiled genes across organoid differentiation. This process involves both generepression and activation. Around 15% of genes are permanently repressed. Many of these, guide cellular differentiation away from neuroectodermic lineages.
- This study reinforces the concept of epigenetic priming in a subset of neuronal genes. Here, chromatin modifications seem to precede gene expression patterns at later developmental stages.
- Chemically inhibiting the writer complex of H3K27me3 alters cellular differentiation trajectories in organoids after 15 days of differentiation, underlining how epigenetic-dependent gene repression is required for the correct unfolding of cell lineage generation during early central nervous system development.
Taken together, these efforts effectively shed light on the intricate interactions between epigenetic patterns and RNA expression during differentiation from pluripotency to neurons. The causal link between histone modification and truthful developmental plasticity restriction upon neuroepithelium expansion was also proven.
Conclusion/why I highlight this preprint
What I liked about this preprint is that all main findings were validated by profiling human fetal cortex samples with scRNA-seq and bulk CUT&Tag. This further confirms biological results in an orthogonal biological model, also emphasizing that organoids are a valuable system to model brain development in vitro. Overall, this comprehensive dataset aims to provide a reference map of human neural epigenomic trajectories, which is now freely available online at https://episcape.ethz.ch. This workflow can be transferred to and exploited in any organoid type, serving as a guide to model physiological organ development and pathogenesis. I thus believe that the work presented in this preprint is of extreme relevance to the field, as it paves the way towards granular omics-based modeling of physiological processes and their pathogenic disruption in organoids.
Questions/future directions
- In this study only H3K27me3 writing was chemically repressed, while it would be interesting to also inhibit the other two histone markers thoroughly characterized in this work. Have you considered doing this?
- After inhibition of H3K27me3 depositing in brain organoids, the outcome of this process was practically assessed only at a very early stage (D15). It would be valuable to employ the same technique to profile later time points, providing a more comprehensive understanding of H3K27me3 depletion effects. Do you have any plans to implement such analysis, or do you believe the current results are sufficient?
- Are there plans to explore the phenotypic effects of H3K27me3 repression? It would be interesting to conduct immunohistochemistry on these organoids, staining for canonical protein markers of the developing brain. Such an approach could reveal alterations in neural processes or morphological changes induced by these perturbations, thereby validating the findings from scRNA-seq and ATAC-seq.
- Have you investigated any enrichment in genes associated with autism spectrum disorders or other neurological impairments following the perturbation of machinery required for proper H3K27 methylation? This inquiry is particularly intriguing considering the well-established link between chromatin remodelers and neurodevelopmental disorders (10).
References:
1. Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M. & Sestan, N. The Cellular and Molecular Landscapes of the Developing Human Central Nervous System. Neuron 89, 248–268 (2016).
2. Seto, Y. & Eiraku, M. Human brain development and its in vitro recapitulation. Neurosci. Res. 138, 33–42 (2019).
3. Cheroni, C. et al. Benchmarking brain organoid recapitulation of fetal corticogenesis. 2022.04.22.488753 Preprint at https://doi.org/10.1101/2022.04.22.488753 (2022).
4. Velasco, S., Paulsen, B. & Arlotta, P. 3D Brain Organoids: Studying Brain Development and Disease Outside the Embryo. Annu. Rev. Neurosci. 43, 375–389 (2020).
5. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).
6. Camp, J. G. et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc. Natl. Acad. Sci. 112, 15672–15677 (2015).
7. Amin, N. D. & Paşca, S. P. Building Models of Brain Disorders with Three-Dimensional Organoids. Neuron 100, 389–405 (2018).
8. Yang, Q., Hong, Y., Zhao, T., Song, H. & Ming, G. What Makes Organoids Good Models of Human Neurogenesis? Front. Neurosci. 16, (2022).
9. Park, J., Lee, K., Kim, K. & Yi, S.-J. The role of histone modifications: from neurodevelopment to neurodiseases. Signal Transduct. Target. Ther. 7, 1–23 (2022).
10. Gabriele, M., Lopez Tobon, A., D’Agostino, G. & Testa, G. The chromatin basis of neurodevelopmental disorders: Rethinking dysfunction along the molecular and temporal axes. Prog. Neuropsychopharmacol. Biol. Psychiatry 84, 306–327 (2018).
doi: https://doi.org/10.1242/prelights.36306
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