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Stem Cells Week 3 Lecture Notes
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ACTIVE DNA METHYLAITON(ARTICLE)
DNA methylation occurs
DNA methylation has been observed during specific stages of development. predominantly in the
DNA methylation process may be achieved by different enzymes and context of CpG (C
mechanisms. followed by G)
The presence or absence of specific epigenetic marks influences gene dinucleotides.
expression, resulting in a transcriptional programme that specifies for a
particular cell type.
In embryonic stem cells, active gene expression marks are found at
pluripotent genes and repressive marks are found at lineage-specific genes. During early development,
Thus, different cell types can be defined by their epigenetic and gene methylation patterns are
expression. initially established by the de
The diversity of genetic material to be regulated necessitates the use of novo DNA methyltransferases
marks corresponding to short-term and ling-term epigenetic memory, DNMT3A and DNMT3B.
depending on the transcriptional requirements of the cell (as well as hose of
future generations).
Developmental genes that are needed during the later stages of development are transiently held
in a repressed state during early development. This is achieved through short-term epigenetic
marks such as histone modifications, which can be removed before or within a few cell divisions.
* Active DNA Demethylation is the enzyme process that results in the removal of the methyl
group from 5-methylcytosine (5meC) by breaking a carbon-carbon bond.
* Passive DNA Demethylation refers to the loss of the methyl group from 5meC WHEN
DNMT1 is inhibited or absent during successive rounds of DNA replication.
METHYLATION DURING EARLY DEVELOPMENT
o Activation of different transcription factors during
gastrulation produces a single cell (zygote) to become all
cells in our body.
o Some genes that are expressed early on into gastrulation
can be switched of after a couple of developmental events
(e.g. the gene is switched on in 1-cell state and closes
during 4-cell state).
o If something goes wrong with the gene transcription, we
will see birth defects.
o In earlier days, pregnant woman would be treated
with thalidomide for morning sickness. Thus,
babies with birth defects on limbs were born.
DNA Elements
- All protein coding genes in the nuclear human
genome are transcribed by RNA polymerase II.
, - RNA polymerase II initiates transcription in conjunction with transcription factors.
- The expression of genes is determined by:
- The availability of transcription factors.
- The accessibility of the DNA element
(promoters/enhancers) to which
transcription factors bind (Methylation
of DNA, Histone modification)
- CpG dinucleotides often cluster in promoter areas.
- Methylated DNA can prevent transcription factors
binding.
- Methylated DNA can recruit proteins which
deacetylate histones.
Regulation of Methylation Marks
* Cytosine residues are methylated
* Regulation of transcription
* Regulation on X-inactivation
* Genomic imprinting
Removal of 5hmC, 5fC, or 5caC through:
1. Replication (active modification, passive dilution (AM-PD)); DNMT1 less efficient at methylating non
5mC strands.
2. Through thymine DNA glycosylase (TDG)/Base
Excision Repair (BER), (Active Modification).
Cooperation of TDG and BER leads to excision of
5fC/5caC and repair to C.
Genomic context-histone
acetylation makes DNA more
accessible to transcription
factors.
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