HDAC Inhibitors

First thing to understand is how DNA makes proteins.


Watch all of these (very short but brilliant) videos, they are pretty much in order.

Summary: A subsection of DNA, say ~1000 base pairs encodes a particular gene. A mechanism (RNA polymerase — http://en.wikipedia.org/wiki/RNA_polymerase) locates the start of this gene, and runs along it all the way to the end, producing an mRNA strand that contains a copy of this data.

The mRNA then exits the nucleus. Then it gets pounced on by a RIBOSOME which is a machine that converts it into a protein.

…. Every triple of base-pairs is called a CODON. Base pairs could be {AT TA CG GC} //(or, if we are just looking at one strand, {A T C G}), so that's 4^3 possible codons. Each codon specifies one of 20 amino acids// (http://en.wikipedia.org/wiki/Genetic_code#RNA_codon_table)

…. So the RIBOSOME is constructing a protein by daisychaining amino acids as per the codon-sequence on the RNA strand.

There is a cunning way of regulating this protein-from-DNA process. DNA (negatively charged) winds around (positively charged) HISTONE spools, and modifying the charge on the histone controls how tightly or loosely it wraps.


(DNA wrapped around histones = chromatin; open chromatin allows transcription)
But if it wraps too tightly, the RNA polymerase machine can't run along the DNA strand, hence can't transcribe the gene (can't make mRNA strand)

https://www.youtube.com/watch?v=N2LbVMcQbLk <— actually promo for some RVX208 drug, but shows all this

Histones have protein-tails, and a compound can attach to a protein-tail that absorbs some of the histone's charge, which will loosen it, allowing transcription. This is called acetylation, or HAT.

However, there is a mechanism for capping this protein-tail so that acetylation can't happen. The mechanism starts with methylation, which causes an HDAC to bind in, which caps the protein-tail.

https://www.youtube.com/watch?v=Tj_6DcUTRnM&list=UUf51VPtCFmXaSlaQP3LJe0A <— beautiful animation of this

So the organism must, as it is growing, alter the HAT/HDAC balance in order to gradually turn off various genes.

(at the moment I can't see how it can do this selectively…)

Wikipedia: 'Acetylation removes the positive charge on the histones, thereby decreasing the interaction of the N termini of histones with the negatively charged phosphate groups of DNA. As a consequence, the condensed chromatin is transformed into a more relaxed structure that is associated with greater levels of gene transcription.'

So, HDACi is a triple negative.
Acetylation causes loosening, which allows transcription, i.e. creation of proteins
HDAC removes this acetylation
Therefore an HDAC inhibitor is something that prevents HDAC from doing it's thing.

So how does the organism choose what gene to express?
https://www.youtube.com/watch?v=MkUgkDLp2iE <— 1500 different transcription factors, and how they search DNA for their particular binding site

https://www.youtube.com/watch?v=vi-zWoobt_Q <— transcription, but starts in the cytoplasm!!!
^ https://www.youtube.com/user/ndsuvirtualcell/videos <— more!

https://www.youtube.com/watch?v=ysxtZJUeTCE <— more detail about enhancer/activator site

- - -

(not so related, but interesting videos worth bookmarking)

https://www.youtube.com/watch?v=nHM4UUVHPQM <— protein synthesis from DNA: not so pretty, but goes as far as protein packing & transport

https://www.youtube.com/watch?v=erOP76_qLWA <— another with protein folding

https://www.youtube.com/watch?v=27TxKoFU2Nw <— much easier to understand DNA replication
^ https://www.youtube.com/channel/UCWZtJoFf-INn0A3j07a4MsA/playlists <— hundreds of videos!!!
^ ^ http://doctorprodigious.wordpress.com/hd-animations/ <— indexed here

https://www.youtube.com/watch?v=cK-OGB1_ELE <— RNAi ?!
^ https://www.youtube.com/watch?v=gnZEge78_78&list=PLc8e2NNCopVuHveOiG0YomKQd1lZpFhsB <— Cell Biology & NeuroScience

Valproate Pitch paper http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848041/#!po=70.0000
Of relevance here is the epigenetic actions of this drug, as enhancing inhibition does not reactivate brain plasticity in adulthood (Fagiolini and Hensch, 2000), but reopening chromatin structure does (Putignano et al., 2007).
^ Last link: Trichostatin A for plasticity!!! http://www.ncbi.nlm.nih.gov/pubmed/17329213

VPA treatment mimics Nogo receptor deletion to reopen plasticity for acoustic preference in mice (Yang et al., 2012), suggesting a common pathway through the regulation of myelin-related signaling which normally closes critical period plasticity (McGee et al., 2005).

https://www.youtube.com/watch?v=FzcTgrxMzZk <— the inner life of a cell

https://www.youtube.com/watch?v=i8c5JcnFaJ0 <— how cells obtain energy

https://www.youtube.com/watch?v=Ao9cVhwPg84 <— cell div, annoying avant garde music

https://www.youtube.com/watch?v=ATlUv-AGhEU&list=PL978360DC8EE52FCB <— CELL CHANNEL

https://www.youtube.com/watch?v=hcGrpd0CRV0&list=PLS5dut9m5mUCiWnG3vHk6zmB1jsXo-_96 <— MAPK signalling — very nice videos

https://www.youtube.com/user/littleying89/playlists <— lots of playlists

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