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Kindle Notes & Highlights
by
Cath Ennis
Read between
January 25 - January 30, 2022
The first step in translating the DNA’s coded instructions is called transcription*.
The process of converting mRNA sequences into proteins is called translation*.
Each three-base unit – called a “codon”* – of mRNA connects to a transfer RNA (tRNA)* strand that has three complementary bases at one end. The other end is attached to a molecule called an amino acid*.
As tRNAs connect to their matching codons along an mRNA strand, their amino acids join up in the same order.
The longest human chromosome contains about 2,600 protein-coding genes; the smallest, just 140. Genes are separated by stretches of non-protein-coding DNA.
The double helix first wraps around a cluster of eight small proteins called histones*, which bind very tightly to DNA. Each individual unit of eight histone proteins plus DNA is called a nucleosome*.
The combination of DNA, histones and scaffold proteins, plus other proteins and RNAs that bind to the overall structure, is called chromatin*.
Before a cell can divide in two, it has to make a second copy of its genome.
The process by which the original fertilized zygote produces all of the body’s cell types is called cell differentiation*.
In 1962, John Gurdon (b. 1933) became the first scientist to artificially reverse cell differentiation. He took the nucleus of a fully differentiated tadpole gut cell and transferred it into a frog’s egg from which the nucleus had been removed. The cloned egg matured into a new, healthy frog. This experiment proved that fully differentiated cells retain all the genetic material needed to produce every cell in the body.
every cell in the human body contains exactly the same DNA as the original fertilized zygote.
Sperm, ovum cells?
Transcription factors bind specific DNA sequences close to genes, and interact with the transcription machinery. The combination of proteins bound to any given gene helps to determine whether transcription takes place.
a few hundred imprinted genes are transcribed from only the maternally-inherited chromosome, and others from only the paternally-inherited chromosome.
The X chromosome contains many more genes than the Y chromosome, and so XX cells have extra copies of some genes compared with XY cells. To compensate for this imbalance, one copy of the X chromosome becomes condensed and inactivated in every XX cell.
unlike imprinting, X chromosome inactivation is random: different cells shut down different copies.
calico
Like imprinting, X chromosome inactivation cannot be explained by transcription factors alone.
the British developmental biologist Conrad Waddington (1905–75). In a paper published in 1942, Waddington merged the older term “epigenesis” with “genetics” to create the new word “epigenetics”.
“mitotic heritability”,
chromatin comprises both DNA and proteins.
DNA and histone modifications represent additional layers of information superimposed onto the DNA sequence. Modern-day epigenetics is the study of this “information” and: • How it is established, maintained and modified; • How its code is translated by the cell; • How it is inherited, both in the short term by the next generations of cells and organisms, and over the much longer periods of time over which evolution takes place; • How it becomes distorted and scrambled in disease; and • How we can read and perhaps learn to edit this information to help improve our health.
The cell uses various RNAs and proteins as epigenetic “highlighters” that establish and maintain the pattern of information, “erasers” that remove it when necessary, and “decoders” that convert the information into usable instructions.
A protein called DNA methyltransferase 1, or DNMT1, is responsible for copying the original DNA methylation pattern to the newly formed strands. DNMT1 recognizes and binds specifically to CpG sites that are asymmetrically methylated. It then adds a methyl group to the naked C base on the new DNA strand, restoring the original cell’s symmetrical methylation pattern. This process is crucial to maintaining the epigenetic landscapes of mature cells and preventing the reversal of cell differentiation. DNA methylation is the best-known example of a mitotically heritable epigenetic modification
passive demethylation is dependent on DNA replication, it can only be used to reactivate silenced genes in cells that are dividing by mitosis.
Sudden gene reactivation is also sometimes needed in mature cells that aren’t currently dividing – for instance, in response to chemicals, temperature changes or other stimuli. Passive dilution of methylation during cell division is unsuitable for these occasions; a separate, active process is needed.
During active demethylation, the methyl groups that need to be removed are tagged with oxygen atoms. “Eraser” proteins called Tet bind specifically to the tagged methyl groups and snip them off the DNA.
the general chaos within human cancer cells includes massive changes in DNA methylation and gene activation patterns
Histone modification patterns change more often, and more quickly, than DNA methylation patterns.
Each nucleosome, on the other hand, is associated with about 150 bases worth of DNA, plus the 80-base linker sequence.
ChIP-Seq* (for “Chromatin Immunoprecipitation Sequencing”) is used to determine which parts of the genome are associated with which kinds of histone modifications
DNA methylation is always associated with gene silencing. In contrast, histone methylation can either silence or activate genes,
Histone acetylation
Histone phosphorylation
Histone ADP-ribosylation
In sperm cells, histones are completely removed from most of the genome and replaced with proteins called protamines, which are smaller than histones and can pack DNA into an extremely compact, inactive form – necessary in such a small cell.
Nucleosomes aren’t fixed in place – they can slide along the DNA. The carefully coordinated disassembly, reassembly and movements of nucleosomes are important components of epigenetic regulation.
Single strands of RNA of any length can pair up with DNA or other RNA strands that contain even very short complementary sequences. Longer RNA strands can also bind to complementary parts of themselves, allowing them to fold up like origami into 3D shapes called “secondary structures”, which can be recognized by certain proteins. RNA molecules use complementary pairing and secondary structures to help coordinate which epigenetic modifications should be made to which parts of the genome.
The longest and most complex RNA molecules that can coordinate epigenetic regulation have the imaginative name of long non-coding RNAs, or lncRNAs
PIWI-interacting RNAs (piRNAs) leave the nucleus after being transcribed and bind to a type of protein called PIWI, which they then bring back into the nucleus.
the smallest known regulatory RNAs have a very imaginative name: microRNAs, or miRNAs*.
mRNA silencing by short complementary RNAs
miRNAs are now widely used as research tools. Targeting an individual mRNA with miRNAs can reveal the role the corresponding protein plays in the cell.
if adding a miRNA makes the cell stop dividing, then the corresponding protein migh...
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It’s much easier to inject a miRNA into a cell to prevent a protein from being translated than it is to ...
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circular RNAs – previously thought to have no function – can also regulate transcription, by mopping up miRNAs so that they can’t block protein translation.
The decoder proteins that bind specifically to methylated DNA and other repressive epigenetic marks have another trick up their sleeves: they can recruit additional highlighter proteins.
The RNAs and proteins that coordinate epigenetic regulation are themselves regulated by epigenetic modifications.
DNA methylation, histone modifications, chromatin remodelling and regulatory RNAs are involved in diverse processes throughout our lives, from the fertilized zygote’s first few cell divisions to the creation of offspring and onwards into old age.
During the next few rounds of mitosis, in the first week after conception, all the cells of the early embryo undergo a drastic epigenetic reset. The overall amount of CpG methylation falls and then starts to climb again, a phenomenon called epigenetic reprogramming
The DNA inherited from the egg cell is passively demethylated as cells divide
