Changes in DNA methylation after exposure to traffic pollution.

Air pollution has been known for a long time to have a significant detrimental effect on the health of many organisms, including humans. Airborne particulates have been linked to cardiovascular diseases, with increases in mortality in relatively short time periods after unusually high incidences of pollution. In separate research, decreases in methylation in blood DNA have been linked to forms of cardiovascular stress. It follows that there may be some observable link between these two separate observations. In this study, a group of scientists from around the world have explored the effects of short term air pollution on blood DNA methylation. There investigations include:

• Testing the effect of exposure to different particulates over periods of between 4 hours and 7 days.

• Testing the effect of seasonal and day-of-the-week variation.

• Comparing results over two different forms of DNA methylation.

http://www.ncbi.nlm.nih.gov/pubmed/19136372

Robert Cope
40977649

Food for thought: novel revelations in human DNA demethylation coupled mechanism discovered in fish

             A rapidly evolving focus in research is the understanding of epigenetic (the superficial inheritable mechanisms of DNA modification) factors contributing to development and malignancy. DNA methlylation is one of the key mechanisms by which epigenetics proceeds, through the prevention of specific gene expression. Explicitly, typical DNA methlylation occurs on the 5 position of cytosine nucleotides (5-meC) occupying (60-90% of) CpG spans of genomic sequence (in mammalian somatic cells). Resultant in altering cellular differentiation, phenotypic expression, and other fundamental cellular function, DNA methlylation is documented to be greatly affiliated with perturbations, such as neoplasia and congenital disorders (e.g. Retts syndrome). Although, much is understood regarding the contributing protein factors performing DNA methylation, little is known with regarding the converse demethlyation process. The zebrafish (Danio rerio) is robust vertebrate model for analysis of genetic cellular development in vivo, due to its small size, high fecundity, and simple husbandry. Amenable to transgenic strategies, the ex utero development of transparent embryos allow for ease of phenotypic analysis and genetic manipulation.

             In a revolutionary study conducted by Rai et al., zebrafish embryos, at the one cell stage were microinjected with a 736 bp hyper-methlyated strand of DNA, to monitor methlylation levels. Elucidation through knockdown and overexpression assays provided evidence of a coupled deamination/ glycosylation mechanism for DNA demethylation. Deamination by either activation induced deaminase (AID) or apolipoprotein B RNA-editing catalytic components (Apobec) alters 5-meC into thymine, resulting in a G:T mismatch. Excision of the thymine is promoted by glycosylation via Mbd4 in a proposed base excision repair-like manner. In fact, overexpression studies actually resulted in demethylation of the zebrafish intrinsic genome, as well as the injected methlyated DNA. Furthermore, the non-enzymatic protein, Gaad45, was found to enhance the interactions and efficacy of the two enzymatic groups, thereby promoting demethylation. As a stepping stone, clarifying a previously unknown, fundamental, natural genetic process regulating epigenetics, the findings of this study provide abundant opportunities for future novel therapeutic strategies to currently incurable DNA methlyation-related diseases.

Lauren Klein (Rygier)

42274593

REFERENCES:

Berman JN, Kanki JP, Look AT. (2005) Zebrafish as a model for myelopoiesis during embryogenesis. Exp Hematol. 33: 997-1006.

Delgado S, Gomez M, Bird A, Antequera F. (2001) Initiation of DNA replication at CpG islands in mammalian chromosomes. EMBO J. 17(8): 2426-2435.

Rai K, Huggins IJ, James SR, Karof AR, Jones DA, Cairns BR. (2008) DNA demethylation in zebrafish involves the coupling of a demainase, a glycosylase, and Gadd45. Cell. 135(7): 1201-1212.

Can a father influence his daughter’s maternal behaviour?

Parental imprinting is an epigenetic mechanism that allows the control of gene expression. At the time of conception, the offspring inherits a copy of each autosomal gene from each parent. However, in a small number of genes found in mammals, one of the two inherited alleles is inactivated.

Peg3 is strongly expressed in the hypothalamus, which suggests that parental imprinting would affect behaviour. Champagne, Curley et al. have recently conducted a study on mice models to explore the role of the paternally expressed gen Peg3 in the behaviour of adult female mice. It was found that the expression of the paternally expressed gene Peg3 is critical for regulating mother-infant interactions. Disruption to Peg3 on mice was demonstrated to have deleterious consequences on important features of maternal behaviour such as nursing and licking/grooming of pups during postpartum period.

In humans, it hasn’t been demonstrated yet that Peg3 has the same behavioural effects, however, similarities on the expression and sequence of this gene in both humans and mice suggests that there could not be radical differences on its function.

REFERENCE: Champagne FA, Curley JP, Swaney WT, Hasen NS, Keverne EB. 2009. Paternal Influence on Female Behavior: The Role of Peg3 in Exploration, Olfaction, and Neuroendocrine Regulation of Maternal Behavior of Female Mice. Behavioral Neuroscience 123: 469-480.

Paola Franco

Do you have the X-Factor? Seems like marsupial and monotreme mammals don’t!

               Inactivation of X chromosome in females is nature’s way of playing fair.  Since females have two X chromosomes and male only one, one of the X chromosomes is inactivated in females to prevent over expression of the same chromosome. This is known as dosage compensation and is a common feature in mammals and is one of the best examples of an epigenetic system. The gene responsible for this is the XIST (X-inactive specific transcript) which is present in the X-chromosome inactivation centre. This gene sequence conserved in most of the mammals is missing in non- eutherian (Non-placental) mammals like marsupials and monotreme (egg-laying). Infact on mapping this region scientists not only failed to find this gene but also the region homologus to it.
        This now leaves us with many questions. Since X inactivation is also seen in non-eutherian mammals if not XIST then what controls it?  Eutherian(placental) and non-eutherian mammals diverged 130 million years ago with monotreme mammals diverged 30 million years before marsupials. So does this mean that X inactivation centre reconstituted in eutherian mammals was independently fused in marsupials and monotreme? This finding though leaves us pondering  about the mechanism and evolution of the epigenetic system confirms one thing ,nature not only likes playing fair but also mysterious...
Lynnmaria Nazareth
42259273

Does the Methylated DNA regions in you equals mean of your mom and dad? Yes, No – come on let’s know about it!

Overall opinion is that monozygotic twins are genetically identical and have no differences in any mechanisms, but studies have demonstrated that a monozygotic twin shows differences at the level of DNA methylation. DNA methylation an epigenetic mechanism plays a major role in the developmental regulation of gene expression. DNA methylation is known to contribute to interindividual phenotypic variations which lead to onset of few diseases. These variations are inherited across generations. Across the majority of the genome, DNA methylation is assumed to be complementary on both alleles, although there are several instances where it can be allele-specific.
Inbred mice are ideally suited to study the inheritance of an epigenetic mark like DNA methylation, because the sameness of genetic backgrounds within a strain allows for reproducible mating conditions between two inbred mouse strains. According to the above statements, when two DNA methylated inbred mice are mated, the F1 hybrid should contain methylated DNA regions from both maternal and paternal. The proportions of methylated regions in the F1 hybrid lead to an interesting concept. Let’s find the secret story...!

Refrences:-
Schilling, E., C. El Chartouni, et al. (2009). "Allele-specific DNA methylation in mouse strains is mainly determined by cis-acting sequences." Genome Research 19(11): 2028-2035.

Saranya Srinivasan
42234328

Functional genomic approach to identify novel genes involved in the regulation of oxidative stress resistance and animal lifespan.

Reducing Reactive Oxygen Species (ROS) production can extend animal lifespan by silencing mitochondrial genes through RNAi mediated. Lower ATP levels may activate genes that regulate worm lifespan. Insulin/IGF-1 receptor-like molecule is supposed to double animal lifespan and genes such as daf-2 encoding this molecule when mutated in Caenorhabtidis elegans can also extend its lifespan.

The authors optimized an assay to monitor ROS resistance in worms using the ROS- generating chemical paraquat. Eighty four genes were identified from chromosomes III and IV by developing a functional genomic RNAi screen. The experiment included C. elegans being cultured in a medium containing bacteria expressing interfering dsRNA for the target gene. The worm was reared until L4 stage and a comparison was made between a culture chemically treated with paraquat and another one non- treated. The species strain was rrf- 3 (pk1426), Polymerase Chain Reaction fragment was cloned in the L4440 vector and primers corresponding to a genomic region in daf- 2 and daf- 18 were obtained.

The study found that mutations in daf2 and daf18 can alter sensitivity toward paraquat toxicity. Moreover a screening method for identification of genes involved in regulation of animal lifespan has been created.

Reference: Yongsoon K,Hong S Functional genomic approach to identify novel genes involved in the regulation of oxidative stress resistance and animal lifespan. (2007) Aging Cell 6, pp 489-503 DOI: 10.1111/J. 1474-9726.2007.00302.x.

Patricia Lemos

New discovery about liver cancer cells: SP1 is an essential aspect for activation and chromatin availability of CD151 promoter

Liver cancer is one of the most common malignant neoplastic diseases today. CD151 gene was known as an influential factor of this cancer’s metastasis. It means that ability to detect liver cancer in diagnostics will be more difficult if the level of CD151 is high. Besides, specific protein 1(SP1) plays activating aspect role in transcription.

By using chromatin accessibility analysis in real-time PCR, Wang and colleagues discovered that there was an open chromatin structure lied in the transcription starting site region of CD151 gene. Before being transferred into HepG2 and Hep3B cells, some fragments in the 5’end of CD151 gene were cut and then it was bound with luciferase reporter gene. They found that SP1 was linked with promoter’s core by manipulating electrophoretic mobility shift assay as well as chromatin immunoprecipitation assay. Their research’s result also showed that the CD151 promoter will completely lost its activity when SP1 was removed.

NGUYEN Thi Thu Hang
41882601

Read more at:
http://www.sciencedirect.com.ezproxy.library.uq.edu.au/science?_ob=ArticleURL&_udi=B6WBK-4YC1K0V-1&_user=331728&_coverDate=03%2F05%2F2010&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000016898&_version=1&_urlVersion=0&_userid=331728&md5=4c38a595bd279357db3b068920c2f4e7

Reversing epigenetics: A potential strategy for treating brain tumor

Recent studies have shown that aberrant epigenetic silencing of anti-tumor genes occurs in various cancers in humans. Foltz et al. have reported two novel tumor suppressor genes namely SDC2 and TMTC1 to be silenced in Glioblastoma multiforme (GBM), the most severe type of brain tumor, by an unusual newly found epigenetic mechanism involving methylation of the histone proteins present in their promoters at their specific tails rather than by the usual epigenetic hypermethylation of the promoter sequences. The expression of these genes was restored in brain tumor cells by inhibiting the methylation process, via silencing of DNA methyl transferases (enzymes that bring about the epigenetic methylation and hence the suppression of these genes) using specific siRNA molecules directed against them. The two genes exhibited growth suppressing anti-cancer effects on brain tumor cells in vitro.

The restoration of expression of epigenetically silenced tumor suppressor genes by inhibiting the methylation of the histone tails in brain tumor cells via the use of specific siRNA molecules targeted against DNA methyl transferases, offers a safe and potential therapeutic strategy to treat brain tumor. Also the epigenetic methylation pattern of these specific genes in the glial cells of the brain and their eventual silencing can be used as a marker for early diagnosis of GBM in patients.

REFERENCE:

Foltz, G., Yoon, J. G., Lee, H., Ryken, T. C., Sibenaller, Z., Ehrich, M., et al. (2009). DNA methyltransferase-mediated transcriptional silencing in malignant glioma: a combined whole-genome microarray and promoter array analysis. Oncogene, 28(29), 2667-2677.


Awais Sharjeel Butt
41971608

Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease

Darwin's theory of evolution is based on the natural selection of genetic variations caused by random mutations. On the other hand, Lamarck suggested that phenotypes are shaped by nature and each individual striving to improve for survival. This paper proposes an alternative theory for evolutionary adaptation based on epigenetics. Epigenetic variations, such as varying DNA methylation patterns, that do not modify the phenotype could nevertheless affect its variability and that increased variability may in turn improve fitness and be passed on. The paper provides two experimental results to support their claims. Firstly, the variations in the extent of DNA methylation in the brain constitute evidence in support of stochastic or random epigenetic variation. Secondly, the loss or gain of CpG dinucleotides over time suggests a transmissible genetic mechanism for DNA methylation.


Christophe Boulay


Feinberg, A. P. and R. A. Irizarry (2010). "Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease." Proceedings of the National Academy of Sciences of the United States of America 107: 1757-1764.

Mechanisms of epigenetic silencing of the Rassf1a gene during oestrogen-induced breast carcinogenesis in ACI rats

Epigenetic changes include alterations of chromatin structure mediated by methylation of cytosine residues in CpG dinucleotides, modification of histones by acetylation or methylation, or changes in higher-order chromosome structure. This phenomenon can be found in many tumouigenesis, including breast cancer.

Starland-Davenport demonstrated that oestrogen-induced breast cancer in rats is associated with an aberrant DNA methylation and increase in trimethylation of histone H3 at Rassf1a promoter. In this study, significant increase of 5-methyl-2’-deoxycytidine content in Rassf1a gene was recorded after 12 weeks of oestrogen exposure, whereas other promoter regions, such as, p16, Socs1, Cx26, and Cdh1, which are usually hypermethylated in human breast cancer, did not show any statistically meaningful increase of methylation level. Moreover, complete loss of Rassf1a protein and significant decrease of Socs1 protein was recorded, which suggested that epigenetic modification of these genes are associated with compromised expression of those genes. Aside from that, the substantial increase of H3K9me3 and H3K27me3 (trimethylation of histone H3 lysine 9 and 27) was registered at the promoter regions of Rassf1a and Socs1 genes. This suggests that trimethylation of histones can contribute to the oncogenesis of oestrogen-induced breast cancer.

Even though breast cancer is generally recognised as the alteration of BRCA1 and BRCA2 gene, this study revealed that there is a close correlation between epigenetic modification of Rassf1a and oestrogen-induced breast cancer in rat model.

Original research paper from; Starlard-Davenport, A., et al., Mechanisms of epigenetic silencing of the Rassf1a gene during estrogen-induced breast carcinogenesis in ACI rats. Carcinogenesis, 2010. 31(3): p. 376-381.


Beomjun Kim

Honeybees Show You Are What You Eat

Scientists have made an interesting new discovery in epigenetics, using honeybees.  When honeybees produce female larvae, these larvae are mostly destined to become workers of the colony, but a few however will grow up to become queens.  Queen bees differ significantly from workers in morphological and physiological traits.  Amongst other differences queens are bigger, their reproductive capabilities are massively greater, they behave differently and they live significantly longer.  Where things start to get really interesting though is that genetically identical female larvae can develop into either a worker or a queen depending on what they are fed.

Larvae destined to become queens are fed a substance called royal-jelly by nurse bees, and this is believed to be the causative agent behind whether a bee develops as a worker or a queen.  Kucharski et al (2008) by injecting small interfering RNA into newly hatched bee larvae, were able to silence the expression of DNA methyltransferase Dnmt3 in the larvae.  Dnmt3 is a key component of DNA methylation and epigenetic control in a range of organisms, and by silencing its expression in the bee larvae they caused the larvae to develope in a manner very similar to as if they had been fed royal-jelly.

These results suggest DNA methylation is used to store epigenetic information in honeybees, that this information can be used in different ways depending on nutrition, and that epigenetic modifications can have profound effects on the developmental fate, behavior, size, reproductive capability and longevity of an organism.

Kucharski, R., Maleszka, J., Foret, R., & Maleszka, R.  Nutritional control of reproductive status in honeybees via DNA methylation. Science, 319, 1827-1830.

Jason Raguse (33710727)

Pregnant Mothers: Folate intake may be beneficial for fetal growth, but can also cause asthmatic complications

Every year, 300 million people are affected with asthma, and the numbers continue to increase. New studies have hypothesized that pregnant mothers taking dietary supplements with folate during the early stages of pregnancy may enhance allergic airways disease in their newborn infants.

Diet supplements rich in folate, are important in protecting the growing fetus from developing facial clefting as well as neural tube and cardiac defects. However, it also contains methyl donors which may affect the expression of transcription factors that control lineage of Th1, Th2 and Treg cells, altering DNA methylation, and affecting genetic expression. This in turn results in the increase risk of a child developing allergic airway disease later on in life.

Scientists have tested out this hypothesis with the use of mice, with both dams and pups exposed to different levels of methyl donor diets. Results have indicated that pups that are fed high-methyl donor diet (HMD) or low-methyl donor diet (LMD) have no significant difference, but dams fed with HMD in utero showed higher signs of their pups developing allergic airway disease. Thus, showing that the period of vulnerability of the fetus is during the gestation period.

With that being said, mothers can be forewarned that taking too much folate supplements during the early stages of pregnancy could put a damper on their child's well being.

Source: Hollingsworth, J, Maruoka, S, Boon,K, Garantziotis, S, Li, Z, Tomfohr, J, Bailey, N, Potts, E, Whitehead, G, Brass, D, and Schwartz, D 2008, 'In utero supplementation with methyl donors enhances allergic airway disease in mice.' Journal of Clinical Investigation. Vol. 118, pp. 3462-3469.

Pei - Yi Yap
42238867

Junk DNA – required for a beautiful mind

If you’ve seen the 2002 Best Picture, A Beautiful Mind, starring Russell Crowe, then you’ll know that “junk DNA” – non-protein related products of the central dogma – are definitely worth examining.

Schizophrenia is a severe and complex neural disorder, and one whose cause and pathology is poorly understood. In the past decade, experimental evidence has strongly implicated the importance of microRNAs (miRNAs – small RNA strands that regulate gene expression) , a type of “junk DNA”, in neural development, function and plasticity.

Kocerha et al. (2009) considered the link between miRNAs and schizophrenia. Previous studies had evidenced decreased NMDA (N-methyl-D-aspartate) glutamate receptor signaling – a neurotransmitter – in neural disorders like schizophrenia. Using a mouse model, they investigated the effect of miRNA expression on the NMDA receptor. Their study showed that the expression of a particular miRNA – miR-219 – is involved in neural disorders that are linked to downregulation of the NMDA receptor.

So, it seems that even “junk” is important for a beautiful mind.

Juliana Ip
42265416

Original article:
Kocerha, J., Faghigik, MA., Lopez-Toledano, MA., Huang, J., Ramsey, AJ., Caron, MG., et al. (2009). MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. PNAS – Proceedings of the National Academy of Sciences of the United States of America, 106 (9): 3507-3512

How Wolbachia bateria feminize its male host?

A sex - changing bacteria can change the sex ratios towards females in offspring born by the infected mother hosts, according to a research of Ilaria Negri, Alberto Alma and their teamers.
A team of researchers from three different Italian universities (Turin, Modena and Milan University) corporately unraveled the ability of the bacteria Wolbachia pipientis in reprogramming the male imprinting in its hosts, the leafhoppers Zyginidia pullula, to increase the rate of infected females in the next generation. Wolbachia pipientis is a trans-generational symbiotic parasite that spreads its infection to the next progeny via the hosts' eggs.
Exception of original structure of the last abdominal segment that is still remained in the feminized males; the bacteria altered the males' characteristics so perfectly that they can become females in the observation of genital structure, sexual mates and even productive ability in some cases.
The teams also discovered there were two kinds of feminized males depending on their testes or ovaries found. However, the feminization only occurred with a threshold of bacterial density.
As an external factor of the leafhopper, Wolbachia can prove that changes regarding environmental factors can be inherited from generation to generation. So, which is your side in evolutionary theory- Lamarck or Darwin?

http://rspb.royalsocietypublishing.org/content/early/2009/04/01/rspb.2009.0324.abstract

Thao Tran

Tiny player join transcription initiation

  In a decade, small non-protein coding RNAs - snoRNAs, miRNAs, siRNAs, piRNAs - have been spotlighted as regulators of gene expression at many pathway and tissues. Each class of small RNAs is classified by specific size, biogenesis, and mechanism, and plays a pivotal role in a wide range of biochemical processes beyond the strong bias that introns are just evolutionary debris. Recently, Taft group suggested a novel class of small RNA which may be common characteristics of the transcription initiation, and therefore named as ‘Transcription initiation RNAs (tiRNAs)’

  In the analysis of human, chicken and drosophila RNA sequences, the length of tiRNAs ranged 12-29 nucleotides, which is relatively shorter than any other classes of small RNAs, and in the collaboration with FANTOM 4 project the modal size of them was identified as 18 nucleotides. Remarkably, tiRNAs map to translation start sites (-60 to +120 nucleotides) and are originated from the same strand with TSSs. Moreover, the association with high G+C promoters and major distribution at downstream of TSSs were also found. Inferring from above evidences, Taft groups proposed that tiRNAs may be the result of RNAPII backtracking and stalling.

Joon Yong An

(42057505)

For more read, http://www.nature.com/ng/journal/v41/n5/full/ng.312.html

Epigenetics and diabetes: understanding the mechanisms that can impact disease progression

Epigenetics is at forefront of experimental understanding of gene expression disruption by environmental influences via post-translation modification of the DNA .  More precisely, modification to the DNA packaging proteins, histones is being investigated.  Histone deacetylase (HDAC)-2 has been implicated recently in the progression of several pathological conditions such as cancer, cardiac hypertrophy and chronic pulmonary diseases.  HDAC acts via decreased acteylation of gene transcription resulting in transcriptional repression.  Although diabetic nephropathy is the most common cause of chronic kidney disease in the Western world, the molecule basis underlying the pathophysiology of diabetic nephropathy is still not entirely understood.  Noh and colleagues (2009) aimed to determine the effect of HDAC inhibition in diabetic kidney, identify the isoforms of HDAC participating in this process and examine the role of reactive oxygen species (ROS) as a downstream signaling molecule mediating diabetes of TGF-beta1-induced dysregulation of HDAC.

Their findings suggest that HDAC-2 plays an important role in the development of extracellular matrix accumulation and epithelial-to-mesenchymal transition in diabetic kidney, both hallmarks of diabetic nephropathy and that ROS mediate TGF-beta1-induced activation of HDAC-2.  These results help strengthen the notion that HDAC may play an important role in the pathogenesis of diabetic nephropathy and may lead to improved understanding of the beneficial effects of HDAC inhibitions for treatment. 

Jennifer Bridge (41005624)

The interaction between p53 and growth-suppressing microRNAs

p53 is a small protein that has a crucial role in the prevention of cancer. Indeed, it is known as ‘the guardian of the genome’. A normal cell goes through a very tightly controlled series of checkpoints during its lifecycle, which helps to ensure that damaged DNA does not get passed on to daughter cells during replication. p53 plays a pivotal role in this ‘quality-control’; if DNA gets damaged (the fundamental problem that causes all cancer), p53 assists in the repair of this damage. If repair is not possible, it forces the cell to ‘commit suicide’.
MicroRNAs are a class of molecule that are only recently being recognised as playing important roles in the regulation of gene expression. They are observed in much smaller amounts in cancerous cells than normal cells, indicating that they may function as ‘tumour suppressors’.
Recently, Japanese researchers discovered an important link between these two molecules. p53 seems to play a modulating role in microRNA maturation, particularly in those microRNAs involved with suppression of cell growth. This has obvious implications for cancer research and potential future treatments.

Read more at http://www.nature.com/nature/journal/v460/n7254/full/nature08199.html

by Adam Frankel (40084761)

Intercellular sugar levels influence rDNA silencing

Following the promising advances in epigenetic, a study from German Cancer Research Center reveals an association between deacetylation and the starvation of cellular glucose which suggest an epigenetic effect on the regulation of ribosomal RNA genes (rDNA) expression. What makes this finding interesting is that such correlation is occurring in a crucial process of eukaryotic cell proliferation, which is ribosomal RNA production.

rDNA expression is supposed to be regulated by both the active and inactive state of SNF2h-containing nucleolar chromatin remodelling complex (NoRC). Shifting rRNA genes to the transcriptional mode occurs by acetylating lysine (K633) at TIP5, which is the major protein in NoRC, bordering to RNA binding sites. Accordingly, this action affects the highly condensed chromatic structure (heterochromatin), nucleosomes positioning and rDNA silencing.
As a reversible action, deacetylation enzyme removes the acetyl group from the lysine (K633). Epigenetically, deacetylase is highly released with glucose starvation to strengthen non-coding RNA (pRNA) binding to its complement sequence in the gene. As a result, rRNA gene becomes silent.

By Yazeed ALDUHAYAN

Skewed X-chromosome inactivation: females affected by autoimmune diseases more often than men

X-chromosome inactivation (XCI) occurs in females to balance the information from the maternal and paternal X-chromosomes. In most instances, it works out to about half the cells in the female expressing the paternal X and the other half the maternal X. However, in some cases skewed XCI can occur resulting in an unbalanced expression from one parental X chromosome.

An autoimmune disease is when your body attacks itself, like your lymphocytes attacking your joints or thyroid gland. This happens far more often in females than males, possibly because of skewed XCI. In this study, researchers extracted and analysed DNA from blood lymphocytes to determine if there was a significant prevalence of skewed XCI in patients with rheumatoid arthritis and autoimmune thyroid disease relative to a control group. What if key immune system cells in a female body were expressed at a skewed rate, for example, 80% from the maternal X-chromosome but only 20% from the paternal chromosome, leading the cells to tolerate other cells expressing the maternal chromosome but more likely to attack the cells expressing the less familiar paternal X-chromosome?  This takes domestic quarrels to a whole new level…



Jennifer Goddard

Micro RNAs: future cancer diagnostic tools and the role of let-7 family on suppression of oncogenes.

Micro RNAs are small RNAs of approximately 19-23 base pairs length or shorter which are produced in all mammalian cells. Micro RNA binds to the complementary mRNA to silence or degrade the activity of target mRNA. A number of studies on human cancers indicate the aberrant behaviour of micro RNA. Recently, research has turned to the evaluation of let-7 mi-RNA as possible biomarkers due to their role in biological processes. One such experiment by Kumar et al. showed the functional inhibition of RAS family and HMGA-2 protein in murine models of lung cancer. The intranasal administration of let-7 mi-RNA into orthotopic mouse and subsequent suppression of tumor (lung adenocarcinoma) cells was termed as a breakthrough in cancer biology and epigenetics.

Microarrays combined with q RT-PCR validation are becoming valuable tools for mi-RNA expression profiling. The most challenging part of the cancer diagnostics processes is to identify the potential biomarkers as early as possible. Let-7 mi-RNA may be used as a potential biomarker in the diagnosis of lung cancer following its expression profile in the early stages of lung cancer. The regulation of let-7 expression and its manipulation may become an interesting futuristic approach to broaden the knowledge of the exact role of this micro-RNA family in tumorigenesis.

Reference: “ Suppression of non-small cell lung tumor development by the let-7 microRNA family”- Kumar et al. (2007)

Bulti Nayak
41846443

Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-deficient diet

Deregulation of epigenetic mechanisms, especially the removal of methyl groups, has been associated with neuropathological disorders. Both hyper- and hypomethylation of DNA and histones have been implicated in modified regulation of gene expression. Normal central nervous system development and function, particularly neurogenesis, depend on status of the one-carbon metabolic pathway and therefore intake of essential nutrients like methionine, choline and folic acid. These one-carbon nutrients are involved in the metabolism of methyl groups that are needed in cellular methylation reactions, and are acquired from S-adenosylmethionine, the primary universal donor of methyl groups in mammals.

The present study examines the epigenetic alterations that occur in the brains of rats, resulting from long term exposure to a diet lacking these essential nutrients. DNA hypermethylation of unmethylated GC-rich DNA domains could be found in brains of folate/methyl deficient rats and was linked to an increase in protein expression of de novo DNA methyltransferase DNMT3a and methyl-CpG-binding protein 2 (MeCP2). High MeCP2 levels in the brain are related to the development of several neurological disorders. Further analysis of the gene expression in the brains of folate/methyl-deficient rats revealed significant changes in expression of 33 genes involved in nervous system development and function.  
Therefore this study indispensably indicates the connection between the status of epigenetic modifications and the functioning of the one-carbon metabolic pathway.

Reference:

Pogribny IP, Karpf AR, James SR, et al.: Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-deficient diet, BRAIN RESEARCH,  2008

Dania Schumann

The regulated role of H19 upstream region in the expression of imprinting genes

Sometimes, one of parents feels jealous when someone tells him that their child takes after their partner. He wonders why the child received the gene from him; but, his gene does not express into phenotype. While his gene is inhibited, his wife’s gene is manifested in the child. This phenomenon is called by the imprinting of gene. So why the only the imprinting gene of one sex is expressed? What factors regulates this process? How the factors allow the expression of this gene but inhibit of another gene?

Stefan Schoenfelder and colleagues interested in the process how imprinting genes were controlled. They focused on researching two specific imprinting genes: H19 and Igf2 (insulin-like growth factor 2). It was suspected that the upstream region of H19 related to the gene expression of H19 and Igf2. To find out the role of the H19 imprinting control region, Stefan Schoenfelder and other scientists transferred the gene encoding this region into Drosophila. Next, they repressed the transcription of H19 imprinting control region in transgenic flies to see what could happen. The result that they discovered was very interesting…


Doan Thanh Tam
s41914548

A new function of DNA methylation----Regulating gene expression in human heart failure

DNA methylation is an epigenetic mechanism which is important in normal organismal development and cellular differentiation in higher organisms. At present, it is discovered that DNA methylation responses to differential gene expression in cells, suppressing expression of viral genes and other deleterious elements and forming of chromatin structure. Additionally, it even play a crucial role in the development of almost all types of cancer. However, it is still unknown that whether the differential DNA methylation correlates with the differential gene expression of Angiogenic factors in Human Heart failure, in spite of the ascertain that other epigenetic mechanisms, such as microRNA and histone modification, which are responsible in this issue.

For comparing ischaemic and idiopathic end-stage cardiomyopathic left ventricular with normal control, Mehregan Movassagh and colleagues performed a preliminary analysis using methylated-DNA immunoprecipitation-chip, validated differential methylation loci by bisulfite-PCR and high throughput sequencing, and identified three gene regions in angiogenic family which can be regulated by DNA methylation, AMOTL2, ARHGAP24, and PECAM1.
Using quantitative RT-PCR and associating with previous study, they found that the genes expression differed significantly between cardiomyopathic hearts and normal control. Shown below:
1 Hypermethylation in the 5’ region of PECAM1 (DMR11) in dilated hearts correlated with decreased expression of PECAM1.
2 Hypomethylation within the gene body of AMOTL2 (DMR24) correlated with reduced expression of AMOTL2.
3 Hypermethylation within the gene body of ARHGAP24 (DMR36) correlated with increased expression of ARHGAP24.
Thus, we can confirm that the differential DNA methylation exists in human cardiomyopathy and it regulates the differential gene expression.

However, we still have to make more effort to investigate more correlated gene regions and unravel the interaction between DNA methylation and special DNA-binding protein regulatory. Moreover, the link between DNA methylation variation and other complex diseases also need to be unravelled.

Reference
Movassagh M, Choy MK, Goddard M, Bennett MR, Down TA, Foo RS. 2010. Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS One 5: e8564

Zhengyang Zhao
42183387

GM-CSF inducesSTAT5 binding at epigentic regulatory sites within the Csf2 promoter of non-obese diabetic(NOD) mouse myeloid cells

Granulocyte-macrophage colony stimulating factor(GM-CSF) is a cytokine signal that can advance the myeloid previous cells into granulocytes, monocytes,macrophages and dendritic cells during their differentiation and the inflammation. The expression of this factor is strictly regulated, and its effection is much more dominant than other two factors, macrophage colony stimulating factor(M-CSF) and granulocyte colony stimulating factor(G-CSF) in myeloid cell differentiation. The response of inflammation in mature myeloid cells is to product GM-CSF that maintain the activation of PGS2 and COX2. GM-CSF is also an inducor of IL- 10 producton. It is believed that cytokine-induced epigenetic control of GM-CSF ‘s DNA coding upstream area involved Csf2 promoter that contain some special sites for the histone deacetylase is playing a vital role to ragulate the resposnsiveness and expression of GM-CSF.

GM-CSF is highly expressed in myeloid antigen presenting cells(APC) in both autoimmune type 1 diabetes(T1D) patients and the non-obese diabetic mouse, which can activate two proteins STAT5A and STAT5B. STAT5 proteins can also be regulated by M-CSF during the expression of myeloid cell DNA, so the over-stimulation of GM-CSF to those two proteins could cause APC‘s lack of responsiveness to M-CSF.

The GM-CSF regulatory function to STAS5 proteins is that it maintains the STAT5 proteins with binding sites on the upstream of GM-CSF coding gene Csf2, an non-coding area that reported as a part of epigenetic chromatin modification sites. It has been testified that in NOD mature macrophages and immature bone marrow cells, STAT5 proteins bind at those sites, which is sitmulated by GM-CSF, can have a positive effection to its own gene expression, and also could explain the highly expressed GM-CSF and the lag of activation of STAT5.

Kai Zhang

 

42114569

Dnmt1 and Dnmt3a two role players of synaptic function and methylation in Neurons

  Dnmt is an alternate name of DNA methyltransferase, and its function is commonly known as transferring a methyl group to DNA. Dnmt1 and Dnmt3a are two important and most abundant family members of DNA methyltransferase. Both Dnmt 1 and Dnmt3a are the key maintenance methyltransferase in human genome, and they usually prefer to methylate CpG in mammalian genome. Also, they plays an important role in DNA imprinting. From previous study, Dnmt1 and Dnmt3a have been considered as important factors of adaptive neuronal gene expression due to the epigenetic mechanisms. However, there is not any proofs or discoveries of these two factors would affect an adult nervous system. Thus, Fan et al. did a further study on how these two DNA methylation factors affect in adult forebrain neurons. The experiment used knockout mice as their research tool, and these knockout mice were divided into Dnmt1 single knockout, Dnmt3a single knockout, and double knockout. Then, they used the DKO mice to compare with two SKO and wild-type mice. As the results, a deficiency of both Dnmt1 and Dnmt3a would cause an unusual neuron size and neural plasticity; deficits in hippocampal learning and memory; upregulation of MHC I and other immune gene expression; Also, an abnormality on DNA methylation partterns in CNS neutrons. Therefore, overlapping of Dnmt1 and Dnmt3a is important for synaptic plasticity, learning and memory, and also maintaining DNA methylation partten in forebrain neurons. However, how these two DNA methyltransferases carry out overlapping function is unclear, but it is possible Dnmt1 and Dnmt3a could be co-operative during the DNA methylation in postmitotic neurons. Thus, a further study is essential for understanding of this regulation pathway.

Reference:

Guoping Fan,. Jiang Feng, et al. (2010). “Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons”. Nature Neuroscience 13:423-430.

Xiang Li

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