Re: Article: Whew! Your DNA Isn't Your Destiny
- From: "whitesickle@xxxxxxx" <whitesickle@xxxxxxx>
- Date: Sat, 20 Aug 2005 01:02:34 -0400 (EDT)
RAGLAND:
Hello Robert. I agree with some of Keim's statements but not with
others or let me just say "we don't know enough yet". In the past I've
written about the importance of epigenetics and I believe even quoted
an epigeneticist who stated before we can unravel or separate the human
DNA genome we must be able to unravel the epigenetics of people. I came
across these definition and short article on epigenetics:
Covers a broad range of effects, and several are discussed in this
special issue. But how did epigenetic regulation arise? For RNA-
mediated silencing and DNA methylation there is evidence that they have
evolved as part of a host defense mechanism against viruses and
parasitic DNA. The substrate - double- stranded RNA (dsRNA) - for both
posttranscriptional gene silencing (PTGS) [or RNA interference (RNAi)]
and transcriptional gene silencing (TGS) seen in plants is a common
intermediate in the life cycle of many viruses and transposons. [Guy
Riddihough and Elizabeth Pennisi, "The Evolution of Epigenetics"
Science 293 (5532): Aug. 20, 2001]
Epigenetics
8/1/03. By RT
Changes to DNA and its associated proteins can alter gene expression
without altering the DNA sequence.
DNA does not exist as naked molecules in the cell: it is associated
with proteins called histones to form a complex substance known as
chromatin.
Chemical modifications to the DNA or the histones alter the structure
of the chromatin without changing the nucleotide sequence of the DNA.
Such modifications are described as epigenetic.
Changes to the structure of the chromatin have a profound influence on
gene expression: if the chromatin is condensed, the factors involved in
gene expression cannot get to the DNA, and the genes will be switched
off. Conversely, if the chromatin is 'open', the genes can be
switched on if required.
While many heritable disorders in humans are caused by DNA sequence
changes (mutations) that abolish gene expression, a number of human
diseases are caused by inappropriate gene silencing, brought about by
epigenetic modifications. Indeed, most cancers involve the epigenetic
silencing of genes that normally control cell proliferation. The major
forms of epigenetic modification occurring in human tumours are DNA
methylation and histone deacetylation.
DNA methylation is a chemical modification of the DNA molecule itself;
it is carried out by an enzyme called DNA methyltransferase.
Methylation can directly switch off gene expression by preventing
transcription factors binding to promoters.
However, a more general effect is the attraction of methyl-binding
domain (MBD) proteins. These are associated with further enzymes called
histone deacetylases (HDACs), which function to chemically modify
histones and change chromatin structure. Chromatin containing
acetylated histones is open and accessible to transcription factors,
and the genes are potentially active. Histone deacetylation causes the
condensation of chromatin, making it inaccessible to transcription
factors and the genes are therefore silenced (see Figure).
Since epigenetic modification plays such an important role in cancer,
novel therapeutic strategies are being developed that are based on the
reversal of DNA methylation and the inhibition of histone
deacetylation. These are being combined with new technologies to
rapidly screen the genome for DNA methylation and histone acetylation
patterns.
However, diseases can also be caused by inappropriate gene activation.
One example is Burkitt's lymphoma, which is caused by the
overactivity of a gene called MYC. In this case, the gene is normally
found in repressed chromatin and is expressed at a low level. Its
function is to promote cell proliferation.
Certain abnormal chromosome rearrangements occurring in lymphocytes
move this gene into a region of open and active chromatin, causing the
production of large amounts of the protein. The result is the
uncontrolled proliferation of lymphocytes, resulting in lymphoma.
RAGLAND:
Everybody has an epigenetic genome. Not just identical twins. I don't
believe socioeconomic status in general has an impact on the epigenome
as Szyf states. Social classes have existed for thousands of years.
Being wealthy and pampered obviously increases your chances of
reproduction and survival than if you are a worker building a pyramid.
Several major diseases have important epigenetic factors and many
people die from them in part. One could consider this natural selection
in the sense of differential reproduction and survival and access to
available resources.
However, many of the modern diseases struck with much less frequency in
the past due to the harsher environment. At least in the affluent and
middle class Western industrialized countries and perhaps elsehere.
Life expectancies in the industrialized West have increased compared to
our evolutionary past. A 70 year old man who has a wife or more than
one and has fathered several children and been in a career position
which afforded him advantageous differential reproduction and survival
and access to resources could hardly be considered a failure by
Darwinian standards. Even a middle class or lower class man who didn't
have as much acess to resources but scored good on the differential
survival and reproduction card would come out looking good although
belonging to different socioeconomic classes.
Although I don't see the origination of the epigenetic code as part of
the DNA nucleotide sequence or code I don't see it as purely
environmental either but a part of Darwinian selection and evolution.
As stated above, "Covers a broad range of effects, and several are
discussed in this special issue. But how did epigenetic regulation
arise? For RNA- mediated silencing and DNA methylation there is
evidence that they have evolved as part of a host defense mechanism
against viruses and parasitic DNA. The substrate - double- stranded RNA
(dsRNA) - for both posttranscriptional gene silencing (PTGS) [or RNA
interference (RNAi)] and transcriptional gene silencing (TGS) seen in
plants is a common intermediate in the life cycle of many viruses and
transposons. [Guy Riddihough and Elizabeth Pennisi, "The Evolution of
Epigenetics" Science 293 (5532): Aug. 20, 2001]
Something is far less than perfect with our epigenetic system today.
The major forms of epigenetic modification occurring in human tumours
are DNA methylation and histone deacetylation. How did this come about?
Is there an extensive record in our evolutionary history of these human
tumours caused primarily be DNA methylation and histone deacetylation?
I mean symptoms which suggest that.
Is it possible that just as our DNA has not really evolved much in ten
thousand years and has created problems for us moderns neither has our
epigenetic system been able to keep pace. Maybe our evolutionary DNA
nucleotide sequence and epigenome in our early evolutionary environment
never intended us to live that long. Just long enough for some of us to
survive and reproduce and the rest die. Nobody can dispute natural
selection doesn't work strongly today as it did in our evolutionary
past. There are way too many people on earth. One can argue a massive
nuclear conflict or a natural or manmade plague sweeping the globe
would be a form of natural selection. It may be but with the technology
as high as it is today and accelerating it will be a more intense
natural selection. The conventional definition of natural selection
would be canceled out since the magnitude of those dying would
certainly include those capable of successful differential reproduction
and survival as well as those not.
But back to my point about how our epigenome has failed. It may not be
merely natural selection but that the way our epigenome evolved never
"intended" us to live as long as we do. This puts the craze of living
immortally into perspective. Just as our DNA nucleotide sequence will
need to be changed so will our epigenome.
Sincerely,
Michael Ragland
P.S. Spare me the list of Octogenerians
Figure
Epigenetic modifications that abolish gene expression. Top panel -
open chromatin is characterized by non-methylated DNA and histones with
acetylated tails. This allows the assembly of transcription factors and
transcription by RNA polymerase. Middle panel - DNA methyltransferase
activity results in the methylation of DNA. This may directly block
binding by transcription factors and prevent transcription. It may also
recruit methyl-binding domain proteins that have associated histone
deacetylases. Bottom panel - DNA methylation and histone
deacetylation result in the condensation of chromatin into a compact
state that is inaccessible by transcription factors.
.
- References:
- Article: Whew! Your DNA Isn't Your Destiny
- From: Robert Karl Stonjek
- Article: Whew! Your DNA Isn't Your Destiny
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