Understanding how our cells develop and specialize into different types is a complex and fascinating area of biology. Scientists know that certain changes, called epigenetic modifications, play a big role in guiding this process. These modifications act like switches that turn genes on or off without changing the actual DNA sequence. However, figuring out exactly how these modifications work has been quite challenging.
In a recent study, researchers at ETH Zürich used models of human brain and retina development called organoids. These organoids are lab-grown tissues that mimic real human organs. The scientists focused on specific epigenetic modifications involving histones, which are proteins that help package DNA in cells. They looked at three types of histone modifications: H3K27ac, H3K27me3, and H3K4me3. Each of these modifications either activates or represses gene expression, helping to control how cells develop and differentiate.
The researchers used a technique called single-cell profiling to examine these modifications in individual cells as they progressed from pluripotent progenitors (cells that can develop into many different cell types) to specialized neural cells in the brain and retina. This allowed them to create a detailed map of the epigenetic changes that occur at each stage of cell development.
Single-cell epigenomic atlas of human brain organoid development from pluripotency to neurogenesis
a, Experimental outline. scCUT&Tag and scRNA-seq were performed at different developmental timepoints during brain and retina organoid development (number of pooled organoids per timepoint: brain: EB (d5): 500, d15: 150, d35: 50, d60: 25, d120: 20, d240: 20, retina: d45: 50, d85: 50). b, Dimensionality reduction and embedding with UMAP of scRNA-seq data with cells colored based on developmental timepoint reveals heterogeneity of cell states and the neuroepithelium as a branching point. c, UMAP embedding of scRNA-seq data with cells colored and labeled by cell state (IP, intermediate progenitor; RGC, retinal ganglion cell; RP, retinal progenitor). d, DAPI staining of an organoid at day 90; scale bar, 1,000 µm (left). One ventricle of an organoid stained for H3K27ac, H3K27me3 and H3K4me3; scale bar, 100 µm (right). This is a representative image. The experiment was performed three times on biological replicates. e–j, UMAP embedding of scCUT&Tag data for H3K27ac (e,f), H3K4me3 (g,h) and H3K27me3 (i,j) colored and labeled by timepoint (e,g,i) or cell state (f,h,j). k–m, Genome browser snapshots of the enrichment of the respective mark (H3K27ac (k) and H3K4me3 (l)—enriched at active genes; H3K27me3—enriched at repressed genes (m)) at four different marker genes (FOXG1—telencephalon, POU5F1—pluripotency, SIX6—retina and AQP4—astrocytes). Each signal track represents the summarized signal of all cells of the annotated cell state. Shaded areas highlight the detected peaks. d, day; Tel., telencephalon; rhomb., rhombencephalon; pro., progenitors; neu., neurons.
One key finding was that the switching between repressive and activating modifications can predict when and how cells will decide their fate. For example, they discovered that removing the repressive H3K27me3 modification at an early stage in neural development (the neuroectoderm stage) disrupted the normal process of cell specialization, causing cells to adopt incorrect identities.
This study provides a comprehensive map of the epigenetic landscape during human neural development. This map is crucial for understanding how different cell types are formed in the brain and retina. By exploring these mechanisms, scientists hope to gain insights into various developmental disorders and diseases, potentially leading to new therapeutic strategies in the future.
This research highlights the importance of epigenetic modifications in guiding the development of diverse cell types in the human brain and retina. By understanding these processes better, we can uncover new ways to address developmental disorders and enhance regenerative medicine.
Zenk F, Fleck JS, Jansen SMJ, Kashanian B, Eisinger B, Santel M, Dupré JS, Camp JG, Treutlein B. (2024) Single-cell epigenomic reconstruction of developmental trajectories from pluripotency in human neural organoid systems. Nat Neurosci 27(7):1376-1386. [article]