Chromatin Architecture and Gorillas...

...probably have little to do with each other as it pertains to our lab's interest.  But, since its been a while since we've had a lab paper/post, I figured that we could indulge in a few articles from today's Nature journal.

The first paper sparked my interest because, 1 -i've been thinking alot more about chromatin dynamics and epigenetics, and 2- I saw this review.  Seems like a good place to start back up...

The second paper is just a fun read.  Its basically the second half of the talk gave by Dr. Hahn last week. Although, I think everyone came because of the first half of her talk on HIV origins. Enjoy.

Lysine 419 targets human glucocorticoid receptor for proteasomal degradation

A very straight-forward and classic approach to characterize a new level of GR protein degradation.

Lysine 419 targets human glucocorticoid receptor for proteasomal degradation

Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors

http://www.nature.com/doifinder/10.1038/sj.bjc.6605810

This group developed a very cool gold-nanoparticles sensors array for the detection of cancer by exhalation. The molecular differences of cancer are expressed also in the production of volatile organic compounds that can be detected in the breath. The sensors array can sense those and can also distinguish between the different types of cancers. Overall it looks like something that can be further developed into a very favorable diagnostic tool for its high sensitivity, and the non-invasiveness.

It is also nice that this group is from Israel!

Nonpromoter DNA methylation by Dnmt3a allows transcription

Dnmt3a-Dependent Nonpromoter DNA Methylation Facilitates Transcription of Neurogenic Genes

This paper showed that Dnmt3a can methylate both promoter and non-promoter DNA regions, with the latter being transcriptionally permissive. Dnmt3a antagonizes Polycomb complex binding and thus the silencing impact by H3K27me3 on transcription. Further, the authors suggested Polycomb may help recruit Dnmt via their direct interaction, and eventually Dnmt activity would be sufficient to counteract the repression by Polycomb. It should be very helpful to pursue how the regulation is coordinated on different genes and during different developmental processes.

Keystone Meeting

A short review on some of the research discussed at this years nuclear receptors keystone symposium:

http://www.nature.com/embor/journal/v11/n8/full/embor2010111.html

ATP-citrate lyase links cellular metabolism to histone acetylation

Sorry for the delay.

What is cool about this paper is that the authors show that global histone aceylation is increased in human colon carcinoma cells grown in the presence of glucose and that this is dependent on the enzyme ATP-citrate lyase (ACL). ACL generates acetyl-CoA from citrate (remember the TCA cycle…how many times did we have to memorize that?) and acetyl-CoA has been shown previously in yeast to serve as the acetyl donor for histone acetyltransferases (HATs). In this paper, the authors also show that adipocyte differentiation, and the gene expression changes that occur, are dependent on ACL. This finding, in addition to previous knowledge that histone deacetylation (via NAD+-dependent Sirtuins) and demethylation (via 2-alpha ketoglutarate-dependent prolyl isomerases) are metabolically regulated, argue that our natural metabolism as well as what we eat influences gene expression through dynamic alterations in chromatin modifications.

If you recall, in p23 overexpressing cells there are increases in metabolically regulated chromatin modifying enzymes (not ACL, but an enzyme that generates acetyl-CoA from long chain fatty acids) and I also see increases histone acetylation at p23 sensitive genes.

GR and MeCP2

So, Freddy sent me a thesis written in 2006 from a German University. It is about a methyl CpG binding protein, called MeCP2, that suppresses GR-target genes. MeCP2 has been shown to be required for the normal function of neurons and is usually thought to act as a repressor of genes, including CRH (my favorite gene). Mutations in the MECP2 gene has been strongly linked to a neurodevelopmental disorder known as Rett Syndrome.

In this paper, they used a microarray analysis to compare gene expression from WT and MeCP2-null mice. They discovered that at least 5 of the 11 differentially regulated genes are GR target genes. They show by ChIP (your favorite technique!) that MeCP2 binds to the promoter region of FKBP5 and SGK1, suggesting a relationship between MeCP2 occupancy and gene expression. Its not very clear to me in the paper, but what is really novel in the thesis is that Dex prevents Mecp2 from binding to a GRE within the FKBP5 gene. This is prevented by RU486. Its in the last figure of the RESULTS Section found HERE.

The bigger picture here, I think, is how epigenetics, in particular, DNA methylation, is regulating the expression of these GR target genes in neurons. This has many implications for stress response since one of the identified genes, POMC, is a key player of the HPA axis and CRH also has been shown to be regulated by MeCP2.

Androgen Receptor Counteracts Doxorubicin-Induced Cardiotoxicity in Male Mice

http://mend.endojournals.org/cgi/content/full/24/7/1338

Doxorubicin, the anticancer drug is used for the treatment of several types of cancer. In many cases the clinical use of Dox is being held back because of its cardiotoxicity. Here the protective role of the AR pathway in the heart is being tested. This group is showing how activation of AR can counteract the damaging effect of Dox.

The nice thing about this is how we keep thinking of AR specifically in prostate cancer and as a drug target that we want to decrease its activation, and here we get an example of the positive role of AR and how targeting its activation in different types of tissues and different types of cancers can do good.

http://www.sciencemag.org/cgi/rapidpdf/science.1189123v1.pdf
http://www.sciencemag.org/cgi/rapidpdf/science.1189123.pdf

The two papers both identified mir-33 as a regulator of cholesterol homeostasis, particularly through its inhibitory effect on ABCA1. Like some other miRs, mir33 lies within the SREBP2 intron and is cotranscribed with SREBP2, thus the regulation of cholesterol level is coordinated. It will be interesting to address mir33 function that is independent of SREBP2, which can be attained, for example, under a condition that SREBP2 proteolysis is blocked but the transcription is still responsive to cholesterol level changes. Another mir (let-7c) potentially targets CCR7, and it is shown in the screen to be affected by cholesterol change in macrophages, whereas in my screen( LXR activated vs not) there is not much change.

A Simple Method for Gene Expression and Chromatin Profiling of Individual Cell Types within a Tissue

This method would require making a transgenic animal, but is a pretty cool method to isolate particular cell types within a tissue to look at gene expression or chromatin structure. I am sure some company will get on it and the mice will be available in a few years.

Also, it has a video that sums up the whole paper and actually shows they guy performing the experiment.

http://www.cell.com/developmental-cell/abstract/S1534-5807%2810%2900249-2

An interesting read...

This is quickly becoming less of the future and more of the present...

The Path to Personalized Medicine

Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009851

This manuscript shows that estrogen conjugates, which cannot enter the nucleus based on size or charge and therefore activate extranuclear estrogen receptor (ER), are protective against cerebral ischemia (i.e. strokes) in rats. The ability of rats to recover learning and memory skills following stroke is improved in the presence of estrogen conjugates and measured using a Morris water maze test, for which I found a cool video on YouTube (gotta love the background music):

http://www.youtube.com/watch?v=LrCzSIbvSN4

The authors associate this observation with increased survival of CA1 hippocampal neurons through increased AKT, ERK, and CREB activation and BDNF production, as well as downregulation of active JNK (known to activate apoptotic pathways).

CDK5 Modulates the Transcriptional Activity of the Mineralocorticoid Receptor and Regulates Expression of BDNF

http://mend.endojournals.org/cgi/content/full/24/5/941#T1

Michael and this same group previously published a paper looking at the effect of cdk5 signaling on GR phosphorylation in neurons. Now they extend their study to MR and the effect of cdk5 on its transcriptional activity. In the process of identifying the phospho-sites induced by cdk5 on MR, they also show that cdk5 induces hGR phosphorylation by mass spec at S267 (one of the same BDNF induced phospho-sites that we identified in our lab).

This paper is not particularly innovative but they do "good" science to address the molecular affects of cdk5 on MR and GR with relevance to action in the nervous system.

LXR as a drug target for Prostate Cancer

http://www.nature.com/onc/journal/v29/n18/full/onc201030a.html

Few interesting studies brought this group to investigate the role of LXR in prostate cancer; LXR is involved in lipid metabolism and cholesterol has a role in tumor development, together with LNCaP xenografts in high cholesterol diet mice that showed increase apoptosis and phospho-signaling.

This group connected the dots and investigated LXR activation in LNCaP in vitro and in vivo and showed very nicely the important role of it in contributing to the cancer apoptosis through downregulation of the AKT pathway.

Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome

Its not the paper of the week...but its been receiving alot of press...

Here's the link

Paper of the Week

GPS2 Is Required for Cholesterol Efflux by Triggering Histone Demethylation, LXR Recruitment, and Coregulator Assembly at the ABCG1 Locus

doi:10.1016/j.molcel.2009.05.006

Week 3/7/10 Paper

Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

my comments will soon follow, thanks!
-MarcusL

Thanks Marcus for setting this up so quickly!
M