Tag Archives: Histone code

Apologies to Hamlet

Apologies to Shakespeare and Hamlet.  Serotonin does “more things in heaven and Earth, Horatio, than are dreamt of in your philosophy.”  How about chemically modifying histones?We all know about serotonin and depression (or at least we think we know).  Block serotonin reuptake by the releasing neuron and bingo you’ve  cured depression (sometimes).  Do not ask the lecturer which of the 15 known serotonin receptors in the brain the increased serotonin actually binds to and what effects the increased levels produce after binding (and which are important for the alleviation of depression).The two body organs producing the most serotonin are the brain and the gut.  Chemical modification of proteins by serotonin has been known for 10 years.  The enzyme responsible is transglutaminase2, it takes the NH2 group of serotonin and replaces the NH2 of glutamine with it — forming an isopeptide bond.

Interestingly, the serotonylation of histones is quite specific.  Only glutamine #5 on histone H3 is modified this way.  For the reaction to occur lysine #4 on histone H3 must be trimethylated (H3K4Me3) — now you can begin to see the combinatorial possibilities of the various histone modifications known.  Over 130 post-ranslational modifications of histones were known by 2013 [ Cell vol. 155 p. 42 ’13 ].

The H3K4Me3Q5Ser is enriched in euchromatin and correlates with permissive gene expression.  Changing glutamine #5 to something else so it can’t be serotonylated changes the transcription pattern, and deficits in cellular differentiation.  You can read more about it in Nature vol. 567 pp. 464 – 465, 535 – 539 ’19 ]

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Omar Khayyam and the embryology of the cerebral cortex

“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