Although it may seem like neurodevelopment and neurodegeneration don’t have much in common, exciting new results on the dynamics of 5hmC in forebrain organoids may just change your mind.
5hmC is enriched in the brain, important in neurodevelopment, and suspected to be relevant to Alzheimer’s Disease (AD) progression. However, due to a lack of human samples and appropriate disease models it has been difficult to study how 5hmC distribution changes during early brain development and AD.
In order to clear up these mysteries, the labs of Zhexing Wen, Jingjing Yang, and Bing Yao at Emory University cultured an iPSC line into forebrain organoids, then assayed 5hmC profiles using hMe-Seal (also known as 5hmC-seq) at 4 different timepoints spanning 112 days. They also conducted 5hmC-seq in cultured organoid models of AD derived from AD patients. Here’s what developed (and degenerated):
- In non-AD forebrain organoids:
- 5hmC peaks are generally found within genes rather than intergenic regions
- There is a drop in the number of 5hmC peaks detected as organoid brain development progresses, with the largest change in peak distribution occurring during the initial transition from embryoid body (EB) to 56 day forebrain organoid
- Differential peaks in the EB phase are enriched for early developmental genes, while peaks specific to later stages of development are enriched for genes key to neurobiological processes and neurodevelopment, like PAX6, AKT1, and SNCA
- There is also a general buildup of 5hmC around enhancer regions identified as being relevant to fetal development, though these enhancers are not necessarily active just yet — they are enriched with H3K4me1 and considered “poised”
- In AD organoids:
- The organoid models exhibit classic features of AD such as accumulation of phosphorylated Tau and Amyloid beta aggregates, making them the earliest models for AD neurodegeneration
- There is a general depletion of 5hmC across the board
- H3K4me3 and H3K27ac marks overlap significantly with differential 5hmC peaks in the AD organoids, suggesting that transcriptional modulation of disease-relevant genes is mediated by 5hmC changes
- Enriched and depleted differential 5hmC peaks overlap significantly with genes related to neurodevelopment and early development, respectively
In general, Keuhner and colleagues demonstrate that 5hmC distribution plays a role in both brain development and degeneration, perhaps through its interaction with other epigenomic features in enhancer regions. These results also suggest that early-life disruption of 5hmC profiles at neurodevelopmental genes increases the risk of AD pathology developing later in life.
For more mind-altering insights, check out the original article in Cell Reports, April 2021.