Methylated cytosines (C) outside CpG islands control gene expression
https://www.sciencedaily.com/releases/2021/04/210416131923.htmExcerpt: "Based on previous work by a group in Italy, the researchers were confident that CRISPRoff would be able to silence specific genes, but they suspected that some 30 percent of human genes would be unresponsive to the new tool.
DNA consists of four genetic letters -- A, C, G, T -- but, in general, only Cs next to Gs can be methylated. To complicate matters, scientists have long believed that methylation could only silence genes at sites in the genome where CG sequences are highly concentrated, regions known as "CpG islands."
Since nearly a third of human genes lack CpG islands, the researchers assumed methylation wouldn't switch these genes off. But their CRISPRoff experiments upended this epigenetic dogma.
"What was thought before this work was that the 30 percent of genes that do not have CpG islands were not controlled by DNA methylation," said Gilbert. "But our work clearly shows that you don't require a CpG island to turn genes off by methylation. That, to me, was a major surprise."
Epigenetic Inheritance Enhances CRISPRoff's Therapeutic Potential
Easy-to-use epigenetic editors like CRISPRoff have tremendous therapeutic potential, in large part because, like the genome, the epigenome can be inherited.
When CRISPRoff silences a gene, not only does the gene remain off in the treated cell, it also stays off in the descendants of the cell as it divides, for as many as 450 generations.
To the researchers' surprise, this held true even in maturing stem cells. Though the transition from stem cell to differentiated adult cell involves a significant rewiring of the epigenome, the methylation marks deposited by CRISPRoff were faithfully inherited in a significant fraction of cells that made this transition.
These findings suggest that CRISPRoff would only need to be administered once to have lasting therapeutic effects, making it a promising approach for treating rare genetic disorders -- including Marfan syndrome, which affects connective tissue, Job's syndrome, an immune system disorder, and certain forms of cancer -- that are caused by the activity of a single damaged copy of a gene."
My comment: Old dogmas are upended again. This discovery emphasizes the role of epigenetic mechanisms and factors in DNA transcription and minimizes the role of the DNA in these cellular processes. This research also confirms that epigenetic changes might be very robust and long standing, even over 450 generations. DNA methylation patterns affect both transcription and alternative splicing procedures so it's one of the most significant factors influencing organismal adaptation and even speciation. However, changes in methylation patterns never result in any kind of evolution. Don't get lost, my friends.