̽��ֱ�� of Cambridge - imprinting

Age of puberty in girls influenced by which parent their genes are inherited from

cjb250 — Wed, 23 Jul 2014 17:00:00 +0000

̽��ֱ��findings come from an international study of more than 180,000 women involving scientists from 166 institutions worldwide, including the ̽��ֱ�� of Cambridge. ̽��ֱ��researchers identified 123 genetic variations that were associated with the timing of when girls experienced their first menstrual cycle by analysing the DNA of 182,416 women of European descent from 57 studies. Six of these variants were found to be clustered within imprinted regions of the genome.

Lead author Dr John Perry at the Medical Research Council (MRC) Epidemiology Unit, ̽��ֱ�� of Cambridge says: “Normally, our inherited physical characteristics reflect a roughly average combination of our parents’ genomes, but imprinted genes place unequal weight on the influence of either the mother’s or the father’s genes. Our findings imply that in a family, one parent may more profoundly affect puberty timing in their daughters than the other parent.”

̽��ֱ��activity of imprinted genes differs depending on which parent the gene is inherited from – some genes are only active when inherited from the mother, others are only active when inherited from the father. Both types of imprinted genes were identified as determining puberty timing in girls, indicating a possible biological conflict between the parents over their child’s rate of development. Further evidence for the parental imbalance in inheritance patterns was obtained by analysing the association between these imprinted genes and timing of puberty in a study of over 35,000 women in Iceland, for whom detailed information on their family trees were available.

This is the first time that it has been shown that imprinted genes can control rate of development after birth.

Dr Perry says: “We knew that some imprinted genes control antenatal growth and development – but there is increasing interest in the possibility that imprinted genes may also control childhood maturation and later life outcomes, including disease risks.”

Senior author and paediatrician Dr Ken Ong at the MRC Epidemiology Unit says: “There is a remarkably wide diversity in puberty timing – some girls start at age 8 and others at 13. While lifestyle factors such as nutrition and physical activity do play a role, our findings reveal a wide and complex network of genetic factors. We are studying these factors to understand how early puberty in girls is linked to higher risks of developing diabetes, heart disease and breast cancer in later life – and to hopefully one day break this link.”

Dr Anna Murray, a co-author from the ̽��ֱ�� of Exeter Medical School, adds: “We found that there are hundreds of genes involved in puberty timing, including 29 involved in the production and functioning of hormones, which has increased our knowledge of the biological processes that are involved, in both girls and boys.”

̽��ֱ��study was supported in the UK by the Medical Research Council and the Wellcome Trust.

̽��ֱ��age at which girls reach sexual maturity is influenced by ‘imprinted’ genes, a small sub-set of genes whose activity differs depending on which parent passes on that gene, according to new research published today in the journal Nature.

In a family, one parent may more profoundly affect puberty timing in their daughters than the other parent

John Perry

Mario Orellana

Race to puberty (cropped)

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Germ cells: the route to immortality

bjb42 — Wed, 01 Apr 2009 15:28:15 +0000

A fertilised egg is potentially immortal since it develops into a new organism that, in turn, can give rise to an endless series of generations. ̽��ֱ��precursors of sperm and eggs, known as germ cells, provide this enduring link between generations because they transmit the parents’ genetic information to the offspring. Precisely how these cells become equipped to reproduce a new organism – and the remarkable erasing and reprogramming steps that happen during this process – is being studied by Professor Azim Surani’s research group in the Wellcome Trust/Cancer Research UK Gurdon Institute, with funding from the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC).

Backing-up the blueprint

Even as the embryo implants in the lining of the womb during pregnancy, a founding population of germ cells is already being set aside within the embryo for the next generation. It’s very important that these cells maintain the ability to form every cell type within the organism – an attribute known as pluripotency and one that is quickly lost from those cells that develop into the rest of the body (skin, neurones, muscle and so on). Studies in Professor Surani’s group have discovered that these primordial germ cells develop in response to a ‘master regulator’ of germ cell fate called Blimp1. This initiates a special germ cell programme that at the same time represses all the other potential cell fates in these cells, leaving intact the blueprint for creating any cell in the body.

Wiping the disc clean

After Blimp1 has halted the march towards development into body cells, the germ cells then proliferate and migrate into fetal gonads, which develop independently at another site in the embryo to form either testes or ovaries. Here, one of the most extraordinary of events occurs that is rather like wiping a hard disc clean and then reloading it with either a maternal or a paternal operating system.

̽��ֱ��critical ‘re-setting’ event wipes out all the pre-existing information and ‘imprints’ that are normally associated with the genetic blueprint that carries the instructions necessary to form the whole organism. This associated information, known as epigenetic modification, is usually required to interpret the genetic information appropriately so that the right genes are selected for expression at the right time during critical cell fate decisions. ̽��ֱ��modifications are ‘imprinted’ and heritable, to denote their maternal or paternal origin.

What the researchers at the Gurdon Institute have discovered is precisely how the erasure process wipes out all the pre-existing epigenetic information and imprints. This leaves the genetic information intact in preparation for new instructions and imprints to be laid down on top of the genetic information – a process that occurs during development of the eggs and sperm in the growing fetus.

How to make eggs and sperm

Our understanding of these processes has now reached such a level that it is possible to make germ cells directly from pluripotent embryonic stem cells, or even from body cells such as skin cells. This naturally raises the prospect that sperm and eggs could be developed directly from body cells in a culture dish. Such innovations might provide new opportunities for applications in reproductive medicine, including exploration of the basis for certain forms of infertility or the underlying causes of cancers such as testicular tumours. But they also raise important ethical issues that will need to be addressed hand-in-hand with progress in the field.

For more information, please contact the author Professor Azim Surani (a.surani@gurdon.cam.ac.uk) at the Wellcome Trust/Cancer Research UK Gurdon Institute. This research was published in Nature (2008) 452, 877–881 and (2005) 436, 207–213.

How do cells become equipped to generate a whole new organism?

Our understanding of these processes has now reached such a level that it is possible to make germ cells directly from pluripotent embryonic stem cells.

Nature (2005), 436, 207-213

Primordial germ cells

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Rethinking the secrets of life: a code upon a code

bjb42 — Sun, 04 Jan 2009 15:29:25 +0000

Cracking the DNA structure in the early 1950s revolutionised the study of genetics in providing key information on how cells transmit information to the next generation. Five decades later, upon the publication of the draft human genome sequence, we entered the so-called post-genomic era. ̽��ֱ��ability to interrogate our complete DNA sequence has allowed a field of genomic medicine to emerge that has had profound promise for our understanding of genetic disease.

But our genomes constitute more than just the linear DNA blueprint. DNA is bundled into three-dimensional chromosome structures. This packaging is influenced by molecular flags known as epigenetic modifications that are attached to the DNA and to the proteins that organise it into chromosomes. These chemical modifications (including methylation and acetylation) determine whether parts of chromosomes are tightly or loosely packaged, which in turn influences whether a gene has the potential to be switched on or off.

Remarkably, during cell division, cells acquire the same epigenetic modifications as their parent cell, resulting in the heritable transmission of these epigenetic states and a ‘memory’ of a cell’s identity. Epigenetic states, however, have inherent flexibility because they can undergo normal regulated change in response to particular stimuli, to modulate gene expression as the need arises; for example, during the development of stem cells into particular organ systems. If these natural epigenetic processes occur improperly, major adverse health and behaviours can ensue. Epigenetic modifications therefore render our genomes functionally flexible, adaptable and vulnerable.

̽��ֱ��study of the epigenetic control of genome function has led to the dawn of a new revolution that some have coined the ‘epigenomic era’. Professor Anne Ferguson-Smith (Department of Physiology, Development and Neuroscience), Dr Miguel Constância (Department of Obstetrics and Gynaecology) and Dr Sue Ozanne (Metabolic Research Laboratories at the Institute of Metabolic Science) are studying epigenetic processes that confer long-term memory to genes under the influence of the cellular environment, with far-reaching implications for human reproduction and health.

An epigenetic voyage in space and time

Epigenetic mechanisms of gene regulation are important throughout development, from when the sperm first meets the egg (fertilisation), through early lineage decisions, to fetal development and postnatal life. Somatic epigenetic modifications need to be ‘reprogrammed’ in germ cells and also in early embryos so as to achieve developmental pluripotency, whereby cells can give rise to all the cells needed in the developing fetus. This normally results in epigenetic marks that are different in some locations on chromosomes inherited from eggs compared with those inherited from sperm.

For 99% of genes inherited by the embryo, gene expression can occur from both the maternally and paternally inherited versions. But the remaining 1% are ‘imprinted’, which means that only one of the two gene copies is expressed after fertilisation. ̽��ֱ��teams of Professor Ferguson-Smith and Dr Constância use imprinted genes as tractable experimental systems for studying the epigenetic control of genome function and its role in mammalian development. Recently, Professor Ferguson-Smith’s team showed that a DNA-binding protein plays a key role in the programming of imprints, providing a link between the underlying DNA sequence and the regulation of epigenetic marks.

Parent power

Why do we need imprinting and what are its evolutionary consequences? ̽��ֱ��Cambridge researchers have discovered that the functional epigenetic asymmetry that exists between the genomes of the parents has important influences during pregnancy and throughout life. These effects include contributions to the allocation of maternal resources – especially to the control of key aspects of mammalian physiology related to growth and adaptations to feeding and metabolism.

Dr Constância’s group has recently described the effects of one gene that is expressed only from the copy inherited from the father. ̽��ֱ��gene for insulin-like growth factor 2 (Igf2) operates in a vital area of the placenta where maternal and fetal blood mix and nutrients are exchanged, controlling the influx of nutrients to the fetus. Igf2 also operates in fetal tissues to control the level of demand for nutrients. These studies raise the novel concept that imprinted genes are key genetic regulators of the supply of, and genetic demand for, maternal nutrients to the mammalian fetus. This may have implications for our understanding of the selective forces that led to the evolution of the process of imprinting.

̽��ֱ��control of nutritional resources is now known to apply to many other epigenetically regulated imprinted genes controlling growth in the mother’s womb and also after birth. Work by Professor Ferguson-Smith’s group has looked in further detail at such genes and has shown that imprinted genes can also influence normal metabolism.

We are what we eat

̽��ֱ��diet of an individual has important health issues at any stage of life – ‘we are what we eat’ after all. There is growing evidence from studies both in humans and in animal models that maternal diet during pregnancy is particularly important as it has major long-term health consequences, including risk of developing type 2 diabetes, heart disease and obesity – so in some ways ‘we are also what our mothers ate’. This has been termed the developmental origins of health and disease hypothesis. It suggests that subtle differences in nutrition or other early environmental factors during fetal or early postnatal life lead to permanent alterations in the structure and function of important organs, leaving a legacy of disease susceptibility in later life.

Dr Ozanne’s group has shown that reducing the protein intake of pregnant rodents leads to type 2 diabetes, obesity and premature death in the offspring. This is accompanied by permanent changes in the expression of genes regulating insulin production and action. All three research teams are currently investigating what the molecular mechanisms could be that connect the effects of maternal diet during pregnancy with gene expression in the offspring many years later (i.e. after many rounds of cell division). Not surprisingly, permanent changes in the epigenetic marks on DNA, and therefore effects on gene programmes throughout development and into adult life, are emerging as a major player. For example, Dr Ozanne and Dr Constância have recently discovered that a reduction in protein intake during pregnancy alters the epigenetic marks on the regulatory regions of important genes in the pancreas, leading to differences in their expression.

DNA wears Prada

Epigenetic processes are not confined to nutrition and growth – many other systems under epigenetic influence are also now coming to light. These include the ability of plants to respond to seasons, the capacity of chromosomes to segregate properly during cell division, and many of the key changes that occur in cancer and neurological disorders. It seems that our genetic future lies not only in studying the skeleton that is our DNA, but also in understanding the epigenetic modifications that clothe it.

For more information, please contact the authors Professor Anne Ferguson-Smith (afsmith@mole. bio.cam.ac.uk; Department of Physiology, Development and Neuroscience), Dr Miguel Constância (jmasmc2@cam.ac.uk; Department of Obstetrics and Gynaecology) and Dr Sue Ozanne (seo10@cam.ac.uk; Metabolic Research Laboratories, Institute of Metabolic Science).

Epigenetics is taking the biomedical research world by storm; three Cambridge scientists use examples from their own research to explain why.

Stefanie Reichelt, Cancer Research UK

large chromosomes

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