In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth.
“The beauty of using organoids is that they allow us to trace back what could happen at the molecular level in early developmental stages,” says lead author Bing Yao, PhD, assistant professor of human genetics at Emory University School of Medicine. “A lot of epigenetic studies on Alzheimer’s use postmortem brains, which only represent the end point of the disease, in terms of molecular signatures.”
The brain organoid model allows scientists to probe human fetal brain development without poking into any babies; they have also been used to study schizophrenia, fragile X syndrome and susceptibility to Zika virus.
Co-author Zhexing Wen helped develop the model, in which human pluripotent stem cells recapitulate early stages of brain development, corresponding to 17-20 weeks after conception. The stem cell lines were obtained from both healthy donors and from people with mutations in PSEN1 or APP genes, which lead to early-onset Alzheimer’s.
Methylation, an epigenetic modification to DNA, can be thought of as a highlighting pen applied to DNAâ€™s text, adding information but not changing the actual letters of the text.
Are you still with me on the metaphors? If so, consider this wrinkle. (If not, more explanation here.)
Emory geneticist Peng Jin and his colleagues have been a key part of the discovery in the last few years that methylation comes in several colors. His lab has been mapping where 5-hydroxymethylcytosine or 5hmC appears in the genome and inferring how it functions. 5-hmC is particularly abundant in the brain.
Methylation, in the form of 5-methylcytosine or 5mC, is both a control button for turning genes off and a sign of their off state. 5hmC looks like 5mC, except it has an extra oxygen. That could be a tag for a removal, or a signal that aÂ gene is poised to be turned on.
Two recent papers on this topic:
Please recall that an enriched environment (exercise and mental stimulation) is good for learning and memory, for young and old. In the journalÂ Genomics, Jin and his team show that exposing mice to an enriched environmentÂ — a running wheel and a variety of toys — leads to a 60 percent reduction in 5hmC in the hippocampus, a region of the brain critical for learning and memory. Â The changes in 5hmC were concentratedÂ in genes having to do with axon guidance. Hat tip to the all-things-epigenetic site Epigenie.
In Genes and Development, structural biologist Xiaodong Cheng and colleagues demonstrateÂ that two regulatory proteins that bind DNA (Egr1 and WT1) respond primarily to oxidation of their target sequences rather than methylation. These proteins like plain old C and 5mC equally, but they donâ€™t like 5hmC or other oxidized forms of 5mC. â€œGene activity could plausibly be controlled on a much finer scale by these modifications than simply â€˜on or â€˜offâ€™,â€ the authors write.
The 2012 Nobel Prize in Medicine was awarded to Shinya Yamanaka and John Gurdon for the discovery that differentiated cells in the body can be reprogrammed. This finding led to the development of â€œinduced pluripotent stem cells.â€
These cells were once skin or blood cells. Through a process of artificial reprogramming in the lab, scientists wipe these cellsâ€™ slates clean and return them to a state very similar to that of embryonic stem cells.Â But not exactly the same.
It has become clear that iPS cells can retain some memories of their previous state. This can make it easier to change an iPS cell that used to be a blood cell (for example) back into a blood cell, compared to turning it into another type of cell. The finding raised questions about iPS cellsâ€™ stability and whether http://www.troakley.com/ iPS cell generation â€“ still a relatively new technique â€“ would need some revamping for eventual clinical use.
Chromosomal hotspots where iPS cells differ from ES cells
It turns out that iPS cells and embryonic stem cells have differing patterns of methylation, a modification of DNA that can alter how genes behave even if the underlying DNA sequence remains the same. Some of these differences are the same in all iPS cells and some are unique for each batch of reprogrammed cells.
Move over, A, G, C and T. The alphabet of epigenetic DNA modifications keeps getting longer.
A year ago, we described research on previously unseen information in the genetic code using this metaphor:
Imagine reading an entire book, but then realizing that your glasses did not allow you to distinguish â€œgâ€ from â€œq.â€ What details did you miss?
Geneticists faced a similar problem with the recent discovery of a â€œsixth nucleotideâ€ in the DNA alphabet. Two modifications of cytosine, one of the four bases http://www.raybani.com/ that make up DNA, look almost the same but mean different things. But scientists lacked a way of reading DNA, letter by letter, and detecting precisely where these modifications are found in particular tissues or cell types.
Now, a teamâ€¦ has developed and tested a technique to accomplish this task.