New type of tumor suppressing gene in breast cancer

Breast Cancer is currently the top 5 cause of death in the world population of women, with about 1 in 8 women would develop breast cancer.The cause of cancer is usually characterised by reactive oxygen species leading to development of cancerous cells.

New analysis indicates that breast cancer cell line have a decreased expression of MnSOD, Manganese superoxide dismutase, an enzymes that catalyses the dismutation of superoxide in the mitochondria, which lead to reduced levels of reactive oxygen species and encoded by the nuclear gene SOD2. In the cases of overexpression of MnSOD decreases the metastatic potential and invasiveness of tumor cell line, this new study suggests that SOD2 gene could possibly be the new type of tumor supressor gene.

Over years of research, it has become clear that epigenetic processes have a critical role in cancer development, in breast cancer cell line where the epigenetic modification of the chromatin structures of SOD2 to become hypoacetylated, leading to decreased binding of transcription factors and therefore lowered production of MnSOD2.
The actual mechanism of the epigenetic regulation of SOD2 gene still remains unclear, requiring further study.


Winnie Yum

Differential Methylation of the X-Chromosome is a Possible Source of Discordance for Bipolar Disorder Female Monozygotic Twins - Araceli Rosa et. al.

Monozygotic twins are twins arising from the same fertilized ovum, and therefore share the same genetic material. Thus, it is expected that they show similar patterns of gene expression. However, studies have shown that variations arise due to epigenetic modifications and might result in differential genetic expression among monozygotic twins. Some of these modifications include methylation of cytosines and histone modification. These modifications could influence the difference in susceptibility between identical twins to diseases such as bipolar disorder and schizophrenia. One such important modification is the chromosome X inactivation. This is highly likely to create a differential expression pattern since during the early stages of development; each of the cells in the female embryo randomly inactivates one X chromosome marked by hyper-methylation of CpG islands early in development, to achieve dosage compensation. This pattern has already been observed in X-linked single gene disorders. The objective of the study was to find out whether this had any linkage in bi-polar disorder (BD) and schizophrenia (SZ) gene expression discordance. DNA was collected from a total of 63 twin pairs, and a PCR targeting the CpG site and a highly polymeric Single Sequence Repeat (SSR) at the human androgen receptor was done, to determine the activation status of the X-chromosome. These samples were either concordant or discordant for BD and SZ. On analysis of these samples, only two pairs of DNA were found to be homozygous for the repeat polymorphism of which one was control and another discordant schizophrenia pair. The study also suggests that pairs of twins discordant for bi-polar disorder may be more discordant for X-linked inactivation patterns, which means that it may be more pronounced in the disorder. This was less pronounced in the schizophrenia pairs of DNA. Also, huge differences were found in the methylation of the maternal and paternal X alleles than concordant twin pairs in the discordant female bi-polar twins. These suggest that the difference in the level of X-chromosome inactivation may contribute to the difference in gene expression levels found in bi-polar disorder in the female monozygotes. Further study in this area, could be done with a larger sample size of monozygotic DNA twin samples with bi-polar disorder and schizophrenia to have a conclusive result.

Prahatha Venkatraman

Epigenetics of Lateralization

Epigenetics of Lateralization

Despite several decades of research, the epigenesis of behavioural and brain lateralization is still elusive, although its knowledge is important in understanding developmental plasticity, function and evolution of lateralization, and its relationship with developmental disorders. Over the last decades, it has become clear that behavioural lateralization is not restricted to humans, but a fundamental principle in the organization of behaviour in vertebrates. This has opened the possibility of extending descriptive studies on human lateralization with descriptive and experimental studies on other vertebrate species. In this review, we therefore explore the evidence for the role of genes and environment on behavioural lateralization in humans and other animals. First, we discuss the predominant genetic models for human handedness, and conclude that their explanatory power alone is not sufficient, leaving, together with ambiguous results from adoption studies and selection experiments in animals, ample opportunity for a role of environmental factors. Next, we discuss the potential influence of such factors, including perinatal asymmetrical perception induced by asymmetrical head position or parental care, and social modulation, both in humans and other vertebrates, presenting some evidence from our own work on the domestic chick. We conclude that both perinatal asymmetrical perception and later social modulation are likely candidates in influencing the degree or strength of lateralization in both humans and other vertebrates. However, in most cases unequivocal evidence for this is lacking and we will point out further avenues for research.

By

Vinodh Narasimhan

ID: 42100254

EPIGENETICINACTIVATION OF RASSF1A IN MALIGNANT CUTANEOUS MELANOMAS

ABSTRACT
RAS is a superfamily of genes that encode for a group of small GTPases. These are involved in various signal transductions. The active form of the proteins eventually interact with another group of proteins which are knows as RAS effector proteins. RASSF1A (RAS association domain family 1A) is gene that encodes one of the RAS effector proteins. This is a tumor suppressor gene. It is associated with cell cycle control, microtubule stabilization, cellular adhesion, motility and apoptosis (Peters, 2007). In another study (Shivkumar,2002), they found that RASSF1A regulates cyclinD1 which is a cell cycle regulator. A mutation in this gene is related to a large number of tumors. In this article, we discuss the inactivation of the RASSF1A gene due to hypermethylation at 2 promoter regions. The study detected that 55% of the tumors show hypermethylation, while all the normal skin sample showed no methylation. Methylation is detected by Methylation Specific PCR(MSP). The RASSF1A gene having hypermethylation in both regions showed no gene expression. The basis for the epigenetic mutation of RASSF1A still remains unclear. But the presence of hypermethylation only in tumor cells indicates the roles of RASSF1A either in the initiation or the progression of the tumors. It has been established that the frequency of hypermethylation of RASSF1A in melanoma tumors is greater than 25%. The discovery of the of the role of RASSF1A in tumors can cause a break through in the developments of anti-cancer drugs.

By

Crystal D'Souza

Dnmt1: Care taker of genomic imprints during pre-implantation development in mammals

Humans have approximately 30,000 genes but show far more complexity than these number of genes can answer to. So, how can the range of variation and depth of complexity observed in humans can be explained? There has to be something more than just the genes. Have you ever thought what causes these variations? And also how these variations inherited from parents are maintained during the development of the embryo? The answer to this is really intriguing.

We mammals are diploid organisms , and our off springs inherit two copies of same gene one from each parent and have the same level of potential to be active in a cell but certain genes show pattern of mono-allelic parental specific gene expression. These genes although have same DNA sequence but show differential expression within the same cell resulting in the variation. The molecular basis to this phenomenon can be best explained by an epigenetic mechanism known as genomic imprinting. Genomic imprinting has the ability to restrict the expression of a gene to one of the two paternal chromosomes. It affects the offspring irrespective of the sex and has significant importance during the developmental process in mammals. Thus the process of DNA methylation, has established the fact how genomic imprinting is achieved in mammals, making it possible to silence one of the parental genes

The process of DNA methylation is controlled by set of enzymes known as DNA methyltransferases- Dnmt1, Dnmt3a and Dnmt3b. Dnmt1 is known to maintain the DNA methylation in somatic cells as inherited from the parents and on the other hand Dnmt3a/Dnmnt3b are responsible for re-establishing the imprints in the germ cells specific to the sex of the gamete, in post-implantation embryos. At the same time it’s also known that during the cleavage stage prior to implantation there is occurrence of global de-methylation. So now the question arises- what maintains the parental specific methylation imprints during the cleavage stage prior to implantation of the embryo? And the reply is the "Dnmt1" enzyme.

The investigation by Hirasawa et al. [2008] showed that the presence isoforms of Dnmt1 in nucleus of oocytes and pre-implantation mice embryos is alone responsible and sufficient enough to maintain parent specific methylation imprints during pre implantation development in mammals.

To learn more about it refer to the main article at http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18559477


Samikshya Biswal
41568400

Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse

In response to stress, the brain signals the adrenal gland to release hormones, including glucocorticoid, and hence its proper levels are important for normal function and to preserve physiological equilibrium. In rats, it has been found that there is a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression. In humans, a recent study by Patrick O McGowan, et al. suggests a link between childhood abuse and decreased hippocampal glucocorticoid receptor expression along with increased hypothalamic-pituitary-adrenal (HPA) activity. They observed that the hippocampal samples from suicide victims with a history of childhood abuse showed increased methylation of the exon 1F NR3C1 promoter, in comparison with suicides with no history of childhood abuse. They suggest that the increased methylation caused lower levels of glucocorticoid receptor to be produced which hindered the capability to handle stress. These altered HPA stress responses may have lead to an increased risk of suicide. The main interpretation for such findings is that childhood adversity might alter the development of systems that serve to regulate stress responses, such as hippocampal glucocorticoid receptor expression, and thus enhance the effect of stress in adulthood and vulnerability for mood disorders. This being proved, the challenge for the future is to understand how epigenetic variation overlaying occurring in nucleotide sequences might explain the developmental origins of vulnerability for chronic illnesses.

 

Sindhu Igoor

Epigenetic reprogramming during wound healing: loss of polycomb-mediated silencing may enable upregulation of repair genes

Epigenetics is an exciting and growing area as can be seen by the increase in research especially in recent years. One area of epigenetics research that is seeing growth is in wound healing. Why would this area be important, especially when you compare it with research related to cancer? Just to give an idea, in USA there are 5 to 7 million people afflicted with chronic wounds and this causes a massive strain on the healthcare services with an annual cost of about US$20 billion. In this sense the importance of research done on the area of Epigenetic reprogramming during wound healing becomes clear, with potential use in the area of gene therapy.
The research shows the un-silencing of repair genes by a group of proteins in cells at the wound-edge. These proteins called the polycomb group (PcG) proteins normally silence the repair genes by methylation of H3 histone protein on the chromatin. During the occurrence of wounds the PcG proteins is downregulated and the repair genes are able to help repair the wound.
Better understanding of wound healing mechanisms may possibly help millions of people have a better quality of life.

Prenatal environment and its relation to risks of diseases

Could your grandmother’s lifestyle and living conditions expose you to higher risk of cancer and metabolic diseases? Studies have been done where data collected from the Dutch Hunger Winter from 1944 to 1945 during World War 2 has shown that man who were fetuses during this period have high risks of getting metabolic diseases further on in life. It has been suggested that the prenatal environment experienced by the fetus gives a prediction of post-natal conditions, thus programming of the fetus phenotype for survival. As for cancers such as breast cancer, leukaemia and hepatoblastoma, various studies done have shown that a child’s birth weight is correlated to the future risk of cancer occurring within the child. From these studies, we can conclude that intra-uterine constraints has a significant role in exposing a child’s risk of developing diseases, however, post-natal environmental conditions would have a final say on the child’s fate.

By Wilson

Review: KDMIB is a histone H3K4 demethylase required to establish maternal genomic imprints

The somatic cells of diploid organisms contain two copies of the genome. With each parent contributing one copy to the offspring. Genomic imprinting is the process whereby one copy of the gene is repressed, such that only the paternally or maternally inherited copy of the gene is expressed. In mammals, imprinting is achieved via methylation of the DNA during gametogenesis in male and female germ cells. The paper by Ciccone et al (2009), demonstrates that demethylation of the histone H3 lysine 4 (H3K4), by the lysine demethylase 1B (KDM1B) is needed to establish DNA methylation imprinting during the late stages of oogenesis. Methylation of the histone H3 protien interferes with the DNA methylation of the loci targeted for imprinting. Thus demethylation of the histone H3 protein may be required to allow better access of the DNA to DNA methyltransferase activity. The paper provides evidence for the role of the KDM1B demethylase in maternal genomic imprinting for several genes examined in the study.

Emily Chan

New targets in breast cancer: the prolyl 3-hydroxylases P3H2 and P3H3

Worldwide, cancers are threatening people’s health and breast caner is one of the most dangerous killers especially for women. According to some study, breast cancer is the second most common type of cancer and the fifth most common cause of cancer death in the world. Therefore, Effective treatments are needed to save lives from this fatal disease. Now, there is good news that comes from R Shah, P Smith and their colleague: the prolyl 3-hydroxylases (enzymes involved in the production of collagen) P3H2 and P3H3 may have the ability to suppress breast cancer. They found that P3H2 and P3H3 are epigenetic silenced specifically in breast cancer because of methylation of CpG islands in their promoters. These phenomena can be associated with positive oestrogen-receptor and higher aggressive level of the disease respectively. Moreover, P3H2 and P3H3 can be expressed ectopically in cells without expression of endogenous gene and suppress the growth of colony. Above evidences indicate that P3H2 and P3H3 are potential specific tumor suppressor of breast cancer.

Promoter specific methylation of the dopamine transporter gene is altered in alcohol dependence and associated with craving

Alcohol dependence is increasingly becoming a social issue. Mesolimbic dopaminergic pathway is responsible for the positive reward that leads to reinforcing action thus causing dependence. In- patient detoxification treatment is now very common. However, the treatment is not easy, due to the withdrawal symptoms and constant alcohol cravings. Epigenetic regulation of alpha- synuclein promoter region via DNA methylation affects dopaminergic neurotransmission, which is involved in alcohol dependence. This reduces the expression of alpha- synuclein which led to lowered alcohol craving. This finding inspired Hillemacher and his group to study the regulation of other genes involved in the dopaminergic neurotransmission in patients with alcohol dependence.

Dopamine transporter (DAT) plays a crucial role in the reuptake of dopamine from synaptic gap to stimulate the mesolimbic dopaminergic reward pathway. The study performed by Hillemacher and his group evaluated the difference in DAT promoter methylation between patients with alcohol dependence and healthy controls. They also established a possible association with alcohol craving.  Promoter specific DNA methylation status of total leukocyte DNA was measured using a methylation specific endonuclease digestion followed by real time PCR. Findings suggest that the DAT promoter is significantly hypermethylated in alcohol dependent patients. Decrease expression of DAT due to hypermethylation of the promoter would lead to elevated levels of dopamine in the synaptic gap. This might be associated with the decrease in alcohol craving.

During the detoxification treatment, abstinence of alcohol was required and this would cause a decrease in DNA methylation, thus leading to alcohol cravings. Alcohol consumption would then lead to the suppression of withdrawal craving.

Alcohol is bad. But we all still love it.

Loh Mun Jo-anne

(s41845512)

Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically

Are you fond of tipple? Do you have any relatives or friends who are really crazy about liquor? Please drink less and request them to drink less. It is universally acknowledged that people who usually consume alcohol are easy to get their liver injuried. Do you know the reason why this phenomenon happens?
Joan Oliva and her colleagues did an experiment about rats that fed ethanol chronically and discovered something that was related to alcoholic liver disease. They demonstrated that chronic ethanol feeding has some connection with an increase in histone acetylation and found out what is the role of proteasome inhibition in the regulation of epigenetic mechanisms of rats. If you want to know more details about this, please visit the following website:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2653439
After you reading this paper, you would able to persuade your family and friends to enjoy less ethanol. Although their just did an experiment on rats, it may be a promising and smart method to study and research liver injury due to chronic ethanol consumption.

Oliva,J.,Dedes,Je.,Li,J.,French,S.W.&Bardag-Gorce,F.2009,Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically.World Journal of Gastroenterology ,15(6): 705-712.

Qiushi Chen
41560637

hSET1: A novel approach for colon cancer therapy

Cancer was and still one of the difficult diseases that has not yet been totally cured. Recently, it has been shown that there are several genetic and epigenetic factors that play major roles in this disease. One of the epigenetic regulations of gene expression in cancerous and normal cells is DNA methylation. This process is achieved by addition of methyl group (CH3) to lysine amino acid at position 9 (K9) or lysine amino acid at position 4 (K4) of the H3 histone. Methylation of K9 will lead to inactivation (silencing) of the gene while methylation of K4 will boost the active state of the gene. Histone-methyltransferaes (HMT) are the enzymes that are responsible for the methylation process. This paper deals with the enzyme histone methyltransferase hSET1 (human SET1) which catalyzes the methylation of H3K4. In this study, Yadav S, Singhal J, Singhal SS, et al found that in malignant cells there is over- expression of hSET1 gene which induces the division and survival of cancer cells. When they used hSET1 antisense* in malignant and normal tissues, they observed a remarkable cell death of maliganant tissue whereas no change occurred for normal cells. Therefore, they suggested that hSET1 could be a new target for tumour treatment.

I hope that this spectacular therapy be available soon in order to alleviate the suffering of many people.


Amjad Yousuf
41892954


Antisense* “Antisense drugs are designed to bind to the mRNA of a target protein, inhibiting the protein production process” http://www.antisense.com.au/_108.asp

SATB1 IN BREAST CANCER EPIGENOME

SATB1 is a special AT-rich binding protein known as a nuclear organizer for the development of tumour cells and promoted metastasis. The study of Han et al on "SATB1 reprogrames gene expression to promote breast tumour growth and metastasis" disclosed that SATB1 is a key factor in breast cancer progression due to to its ability in regulating gene expression via chromatin remodelling. Both invitro and invivo methods were used to test for the function of this protein in breast cancer development. The results in this study showed that SATB1 acts as an activator for the promotion of aggressive cancer phenotypes and metastasis. Key epigenetic progress for this tumour progression is the formation of chromatin loop for transcription process resulting in targeting chromatin remodelling and regulating histone modification.

Han, HJ., Russo, J., Kohwi, Y. & Kohwi-Shigematsu, T. (2008). SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature. 452:187-193

Dinh Hoang Lan Chi,
41614987

The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer.

Epigenetics of human cancer is a challenging but promising area for early detection, prognosis, and therapy. In virus-associated cancers, interaction between pathogens and hosts leads to epigenetic modification in which genomes of specific viruses and the infected cells are regulated by a variety of mechanisms including DNA methylation, histone modifications, and binding of regulatory proteins. The epigenetic reasons why viral pathogens escape from the human immune system and how human infected tissues progress to cancer are not completely investigated. In this article, Fernamdez et al. (2009) has used bisulfite genomic sequencing of multiple clones to describe the DNA methylation in every CpG nucleotide position in the genome of Human Papilloma Viruses 16 and 18, which are responsible for most uterine cervical cancers; as well as Human Hepatitis B Virus and in all the transcription start sites of the Epstein-Barr Virus (EBV). Most interestingly, the level of methylation in the genomes of these viruses was associated with the progress of the disease from asymptomatic through chronic to tumour invasive stages. The evidence of viral adaptation by integration and methylation in the host genomes could stimulate the progress of ongoing human epigenome projects for further understanding of any alternation in human genome that drives to carcinogenic changes.

My Ngoc Nghiem
ID: 42136860

Investigation of the role of epigenetic modification of the rat glucokinase gene in fetal programming.

Fetal environment (or fetal programming) plays an important role in the development of many organisms. At the molecular genetic level, it can also alter the expression of many genes, which will lead to the developmental disabilities such as the development of impaired glucose tolerance, diabetes and hypertension in many mammalian species, including human. In this paper, Bogdarina et al. proposed that DNA methylation could be one of the potential mechanisms that help to explain the association between the maternal low protein diet and the expression of hepatic glucokinase gene. Their findings suggest that programming may influence methylation pattern in Gck at a distance from the promoter, or in genes coding factors that regulate basal Gck expression.

Uyen Tran
ID: 41987494

Increased Life Span due to Calorie Restriction in Respiratory-Deficient Yeast

Calorie restriction (CR) is a moderate reduction of energy intake for organisms. The response to CR has been shown to slow aging in many species like yeast, worms, flies and rodents. One of the potential mechanisms is that CR will cause a metabolic shift of yeast from fermentation to respiration. As a result, it activates a NAD+-dependent histone desacetylase Sir2, and Sir2 further slows down aging. In this study they found that life span extension by CR in both long life span and short life span strain yeast is independent of respiration.

An alternative mechanism is that CR decreases the expression level of Sir2 inhibitor nicotinamide. This study found that addition of nicotinamide to the medium will dramatically shortens the life span of wild type cells, but only partially prevent life span extension in cells lacking both Sir2 and replication fork block protein Fob1 by CR.

Yi-Lin Cheng
42134932

Folate supplementation affects asthma risk in offspring?

Since the discovery of the link between insufficient folic acid and congenital abnormalities, pregnant women worldwide have been recommended by governments and health organizations to supplement their diets with folate. Coincidentally, along with the worldwide campaigns for pregnant women to have diets supplemented with folate, the prevalence of allergic asthma in humans has increased.

While being an important nutrient for pregnant women to protect against a number of congenital abnormalities in their fetus, folate is also a source of methyl donors which could affect genetic expression by altering DNA methylation within regulatory regions of genes.

In their experiment, Hollingsworth’s group fed mice a methyl donors-supplemented diet during gestation and weaning. They found that maternal dietary intake of methyl donors enhanced the development and severity of allergic asthma in the F1 progeny as well as the F2 generation mice.

This study suggested that the increase in prevalence of allergic asthma may in part be related to increased folate supplementation amongst pregnant women. However, because of the importance of folate supplementation to prevent congenital abnormalities and the limitations of directly applying mouse model findings to humans, further research of dietary supplementation during pregnancy is required before changes to current recommendations are considered.

By

Zai yang Phua
41090714

The transgenerational effects of prenatal exposure to the Dutch famine –neonatal adiposity and adult obesity. Would epigenetic changes express to next generation?

The Dutch famine occurred in the Western Netherland during year 1944~1945, which was the end of World War II. Over this period, around 18000 people died in this famine. Scientists found out the children whose mothers were exposed to the famine during pregnancy were lighter and shorter than those whose mother did not suffer from the famine. But what's the influence of Dutch famine on these famine-exposed children?

Experiments indicate environment could induce the change of human health traits, such as obesity, diabetes, cardiovascular disease or other diseases, without changing human genome. By doing historical cohort studies of Dutch famine, evidence shows the prenatal exposure to famine increase the chronic disease in not only next generation but also the subsequent generation.

The mystery of epigenetics is not yet well understood. However, there is one hypothesis which could explain the link between environmental contribution (famine) and health trait change (obesity and diabetes) - the thrifty epigenotype hypothesis.


Hui-wen Lin

41925526

Epigenetic control of skull morphogenesis by histone deacetylase 8

The field of epigenetics is primarily concerned with the ability for genes to be turned “off” or “on” – in other words, the study of how genes can be made accessible or inaccessible by the body and how that affects development, functioning and regulation of important biological processes. One of the major groups proteins which prevents ‘access’ of a gene, are called Histone deacetylases, whose primary effects are to tighten chromatin, preventing genes on that chromatin from being expressed in cells.

This paper, entitled Epigenetic control of skull morphogenesis by histone deacetylase 8, by Haberland, Mokalled, Montgomery and Olson, 2009, examines the role of a Histone deacetylase 8 (Hdac8) in skull formation in mice. The team created a mouse with a Hdac8 deletion, resulting in severe deficiency of Neural Crest Cells (NCCs) resulting in a loss of cranial bone structure – thus the Hdac8 mutation is lethal. The Hdac8 mutant NCC cells were examined and it was found that pathways related to neurogenesis and the production of cytoskeletal proteins were upregulated.

The paper identifies two genes, Otx2 and Lhxl, which are affected by the lack of Hdac8, which could be at the root of the frontal skull dysmorphism.
The paper also examines implications for human health – Hdac inhibitors, a relatively recent class of medicines, have been implicated as a possible cause of increased occurrences of facial abnormalities in infants born from mothers taking such inhibitors.

By

MARK PHILLIPPS

40995867