“The moving finger writes; and, having writ, moves on”. Did Omar Khayyam realize he was talking about the embryology of the human cerebral cortex? Although apparently far removed from chemistry, embryology most certainly is not. The moving finger in this case is an enzyme modifying histone proteins.
In the last post (https://luysii.wordpress.com/2018/06/04/marshall-mcluhan-rides-again/) I discussed how one site in the genome modified the expression of a protein important in cancer (myc) even though it was 53,000 positions (nucleotides) away. When stretched out into the usual B-form DNA shown in the text books this would stretch 1.7 microns or 17% of the way across the diameter of the usual spherical nucleus. If our 3,200,000 nucleotide genome were chopped up into pieces this size some 60,000 segments would have to be crammed in. Clearly DNA must be bent and wrapped around something, and that something is the nucleosome which is shaped like a fat disk. Some 160 or so nucleotides are wrapped (twice) around the circumference of the nucleosome, giving a 10fold compaction in length.
The nucleosome is made of histone proteins, and here is where the moving finger comes in. There are all sorts of chemical modifications of histones (some 130 different chemical modifications of histones are known). Some are well known to most protein chemists, methylation of the amino groups of lysine, and the guanido groups of arginine, phosphorylation and acetylation of serine and threonine. Then there are the obscure small modifications –crotonylation, succinylation and malonylations. Then there are the protein modifications, ubiquitination, sumoylation, rastafarination etc. etc.
What’s the point? All these modifications determine what proteins and enzymes can and can’t react with a given stretch of DNA. It goes by the name of histone code, and has little to do with the ordering of the nucleotides in DNA (the genetic code). The particular set of histone modifications is heritable when cells divide.
Before going on, it’s worth considering just how miraculous our cerebral cortex is. The latest estimate is that we have 80 billion neurons connected by 150 trillion synapses between them. That’s far too much for 3.2 nucleotides to explicitly code for.
It turns out that almost all neurons in the cerebral cortex are born in a small area lining the ventricles. They then migrate peripherally to form the 6 layered cerebral cortex. The stem cell of the embryonic cortex is something called a radial glial cell which divides and divides each division producing 1 radial glial cell and 1 neuron which then goes on its merry way up to the cortex.
Which brings us (at last) to the moving finger, an enzyme called PRDM16 which puts a methyl group on two particular lysines (#4 and #9) of histone H3. PRDM16 is highly enriched in radial glia and nearly absent in mature neurons. Knock PRDM16a out in radial glia, and the cortex is disorganized due to deficient neuronal migration. Knock it out in newly formed neurons and the cortex is formed normally. The moving finger having writ (in radial glia) moves on and is no longer needed (by mature neurons). “nor all thy Piety nor Wit shall lure it back to cancel half a line. Nor all thy tears wash out a word of it”.
You may read more about this fascinating work in Neuron vol. 98 pp. 867 – 869, 945 – 962 ’18
Chemiotics II 