Transcript Epigenetics - Current Issues in Human Genetics

Epigenetics
Memory, Learning and BDNF gene expression
Epigenetics Overview:
I. Mechanism for stable maintenance of gene expression that
involves physically 'marking' DNA or its associated proteins.
A. Addresses issues of where, when & how gene is
expressed
B. May play critical role in cancer,
depression, psychosomatic diseases & memory formation.
1. If an identical twin has cancer it does not mean their
"clone" will as well.
Mechanisms
1. Tagging of Histones
a) Acetylation: Gene expression activated
during
transcription
b) Phosphorylation: activated
c) Ubiquitylation: silenced
2. DNA changes:
a) Methylation: Downregulation of
transcription (silenced): (Jirtle 2003)
3. RNAi: disrupts gene expression
a) non-coding RNA
b) X-chromosome inactivation
c) Circadian Rhythmicity
The Epigenome and LTP
Junko et al (2009)
I. Long Term Potentiation (LTP): EPSPs that last > 10 min. due
to upregulation of receptors that depolarize the cell. WOW!
A. Mice bred null for ras-grf1/ ras-grf 2 vs. control wildtype
1. 1/2 of each group exposed to EE
-Magnitude of LTP remains high for MONTHS in EE
mice!
2. 15 day old mice exposed to 14 days of EE and allowed
to mate
-WE CAN CHANGE OUR
DESTINY!!
Brain-Derived Neurotrophic Factor
(BDNF)
- Important for neurons to grow and connect to each other,
and contributes to long-term potentiation
- Both are part of "neural plasticity" = the ability of the brain to
change as a result of experience
-Shown in aplysia that long term memories cannot be formed
when BDNF is blocked (University of California - Irvine (2006, September 6). Proteins Necessary
For Brain Development Found To Be Critical For Long-term Memory. ScienceDaily. Retrieved May 5, 2011, from
http://www.sciencedaily.com/releases/2006/09/060905225522.htm)
"Epigenetic Regulation of bdnf Gene
Transcription in the Consolidation of Fear
Memory" (Lubin et al, 2008)
Experiment:
3 groups of rats:
1) fear conditioned = associative contextual conditioning
2) naive = novel context learning
3) shock-alone
mRNA levels were measured in the CA1 region of
hippocampus 0.5, 2, and 24 hours after conditioning and
DNA methylation changes at bdnf gene were measured
Results
* site-specific initiation of bdnf transcription
- associative fear conditioning = increase in
exon
IV-containing transcripts
- context learning = exon I and VI transcribed
*DNA methylation consistent with bdnf transcription
"Lasting Epigenetic Influence of
Early-Life Adversity on the BDNF Gene"
Experiment:
(Roth et al, 2009)
-Stress-induced changes in behavior may be connected to
changes in neural plasticity in prefrontal cortex (PFC) and the
hippocampus
-Newborn rats were exposed to a stressed-abusive mother, a
positive caregiving mother, or their own natural mother
RESULTS
- Rats with adverse early-life experiences showed an
increase in methylation and decrease of expression of BDNF
gene in PFC, which lasted into adulthood
- Maltreatment (initially) caused increase in mRNA levels in
hippocampus, as did rats who were exposed to positive
caregiving mothers exposure to new things!
-increased methylation of BDNF gene was passed on to next
generation
Conclusion
Epigenetics plays an important role in memory and learning.
- selective methylation at bdnf gene in hippocampus
and
PFC
Epigenetic changes can be maintained, and even inherited.
Understanding epigenetic mechanisms could lead to improved
treatments for a wide array of illnesses, both physical and
psychiatric.
Some treatments already available....
Sources
Holt. (2007). Epigenetics:Environmental factors can alter the way our genes are expressed, making even
identical twins different. PBS. NOVA.
Junko, et. al. (2009). Transgenerational Rescue of a Genetic Deficit in LTP and Memory Formation by
Juvenile Enrichment. Journal of Neuroscience. 1496-1502.
Cloud, J. (2010). Why Your DNA Isn't Your Destiny. New York Times.
University of California - Irvine (2006, September 6). Proteins Necessary For Brain Development Found To
Be Critical For Long-term Memory. ScienceDaily. Retrieved May 5, 2011, from
http://www.sciencedaily.com/releases/2006/09/060905225522.htm
Lubin, F. D., Roth, T. L., Sweatt, D. (2008). Epigenetic Regulation of bdnf Gene Transcription in the
Consolidation of Memory. The Journal of Neuroscience. 10576-10586.
Roth, T. L., Lubin, F. D., Funk, A.J., Sweatt, D. (2009). Lasting Epigenetic Influence of Early-Life Adversity
on the BDNF Gene. Biol Psychiatry. 760-769.