̽��ֱ�� of Cambridge - Miguel Constancia

Unborn babies use ‘greedy’ gene from dads to ‘remote-control’ mums into feeding them extra food

Anonymous — Tue, 11 Jul 2023 15:00:32 +0000

̽��ֱ��unborn baby ‘remote controls’ its mother’s metabolism so the two are in a nutritional tug of war. ̽��ֱ��mother’s body wants the baby to survive but needs to keep enough glucose and fats circulating in her system for her own health, to be able to deliver the baby, breastfeed and to reproduce again.

A new study from the ̽��ֱ�� of Cambridge published today examines how the placenta communicates with the mother through the release of hormones so she will accommodate her baby’s growth. ̽��ֱ��placenta is a vital organ that develops with the fetus in pregnant women and other female mammals to support the developing fetus. In pregnant mice, scientists selectively altered the signalling cells in the placenta that tell mothers to allocate nutrients to her developing fetuses.

Professor Amanda Sferruzzi-Perri, Professor in Fetal and Placental Physiology, a Fellow of St John’s College and co-senior author of the paper, said: “It’s the first direct evidence that a gene inherited from the father is signalling to the mother to divert nutrients to the fetus.”

Dr Miguel Constancia, MRC Investigator based at the Wellcome-MRC Institute of Metabolic Science and co-senior author of the paper, said: “ ̽��ֱ��baby’s remote control system is operated by genes that can be switched on or off depending on whether they are a ‘dad’s’ or ‘mum’s’ gene’, the so-called imprinted genes.

“Genes controlled by the father are ‘greedy’ and ‘selfish’ and will tend to manipulate maternal resources for the benefit of the fetuses, so to grow them big and fittest. Although pregnancy is largely cooperative, there is a big arena for potential conflict between the mother and the baby, with imprinted genes and the placenta thought to play key roles.”

̽��ֱ��findings by researchers from the Centre for Trophoblast Research at Cambridge’s Department of Physiology, Development and Neuroscience and the Medical Research Council Metabolic Diseases Unit, part of the Wellcome-MRC Institute of Metabolic Science, have been published in Cell Metabolism.

̽��ֱ��baby’s genes controlled by the father tend to promote fetal growth and those controlled by the mother tend to limit fetal growth.

Professor Sferruzzi-Perri explained: “Those genes from the mother that limit fetal growth are thought to be a mother’s way of ensuring her survival, so she doesn’t have a baby that takes all the nutrients and is too big and challenging to birth. ̽��ֱ��mother also has a chance of having subsequent pregnancies potentially with different males in the future to pass on her genes more widely.”

Researchers deleted the expression of an important imprinted gene called Igf2, which provides instructions for making a protein called ‘Insulin Like Growth Factor 2’. Similar to the hormone insulin, which is responsible for making and controlling glucose levels in our circulation, the gene promotes fetal growth and plays a key part in the development of fetal tissues including the placenta, liver and brain.

Dr Jorge Lopez-Tello, a lead author of the study based at the ̽��ֱ��’s Department of Physiology, Development and Neuroscience, said: “If the function of Igf2 from the father is switched off in signalling cells, the mother doesn’t make enough amounts of glucose and lipids – fats – available in her circulation. These nutrients therefore reach the fetus in insufficient amounts and the fetus doesn’t grow properly.”

̽��ֱ��scientists found that deleting Igf2 from the placenta’s signalling cells affects the production of other hormones that modulate the way the mother’s pancreas produces insulin, and how her liver and other metabolic organs respond.

“We found Igf2 controls the hormones responsible for reducing insulin sensitivity in the mother during pregnancy. It means the mother’s tissues don’t absorb glucose so nutrients are more available in the circulation to be transferred to the fetus,” said Professor Sferruzzi-Perri.

Babies with Igf2 gene defects can be overgrown or growth-stunted. “Until now, we didn’t know that part of the Igf2 gene’s role is to regulate signalling to the mother to allocate nutrients to the fetus,” added Professor Sferruzzi-Perri.

̽��ֱ��mice studied were smaller at birth and their offspring showed early signs of diabetes and obesity in later life.

Professor Sferruzzi-Perri said: “Our research highlights how important the controlled allocation of nutrients to the fetus is for the lifelong health of the offspring, and the direct role the placenta plays.

“ ̽��ֱ��placenta is an amazing organ. At the end of pregnancy, the placenta is delivered by the mother, but the memories of how the placenta was functioning leaves a lasting legacy on the way those fetal organs have developed and then how they’re going to function through life.”

̽��ֱ��next step is to understand how placental hormones are controlled by Igf2 and what those hormones are doing. Future research could help scientists discover new strategies to target the placenta to improve health outcomes for mums and babies.

Mice are used in research because the organisation of their DNA and their gene expression is similar to humans, with ninety-eight percent of human genes having a comparable gene in the mouse. They have similar reproductive and nervous systems to humans, and suffer from many of the same diseases such as obesity, cancer and diabetes.

Reference
Lopez-Tello, J et al. Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene. Cell Metabolism; 11 July 2023; DOI: 10.1016/j.cmet.2023.06.007

Adapted from a press release from St John’s College Cambridge

A study in mice has found that fetuses use a copy of a gene inherited from their dad to force their mum to release as much nutrition as possible during pregnancy.

It’s the first direct evidence that a gene inherited from the father is signalling to the mother to divert nutrients to the fetus

Amanda Sferruzzi-Perri

Understanding Animal Research

Brown mouse

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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‘Battle of the sexes’ begins in womb as father and mother’s genes tussle over nutrition

cjb250 — Mon, 27 Dec 2021 16:00:07 +0000

As the fetus grows, it needs to communicate its increasing needs for food to the mother. It receives its nourishment via blood vessels in the placenta, a specialised organ that contains cells from both baby and mother.

Between 10% and 15% of babies grow poorly in the womb, often showing reduced growth of blood vessels in the placenta. In humans, these blood vessels expand dramatically between mid and late gestation, reaching a total length of approximately 320 kilometres at term.

In a study published today in Developmental Cell, a team led by scientists at the ̽��ֱ�� of Cambridge used genetically engineered mice to show how the fetus produces a signal to encourage growth of blood vessels within the placenta. This signal also causes modifications to other cells of the placenta to allow for more nutrients from the mother to go through to the fetus.

Dr Ionel Sandovici, the paper’s first author, said: “As it grows in the womb, the fetus needs food from its mum, and healthy blood vessels in the placenta are essential to help it get the correct amount of nutrients it needs.

“We’ve identified one way that the fetus uses to communicate with the placenta to prompt the correct expansion of these blood vessels. When this communication breaks down, the blood vessels don’t develop properly and the baby will struggle to get all the food it needs.”

̽��ֱ��team found that the fetus sends a signal known as IGF2 that reaches the placenta through the umbilical cord. In humans, levels of IGF2 in the umbilical cord progressively increase between 29 weeks of gestation and term: too much IGF2 is associated with too much growth, while not enough IGF2 is associated with too little growth. Babies that are too large or too small are more likely to suffer or even die at birth, and have a higher risk to develop diabetes and heart problems as adults.

Dr Sandovici added: “We’ve known for some time that IGF2 promotes the growth of the organs where it is produced. In this study, we’ve shown that IGF2 also acts like a classical hormone – it’s produced by the fetus, goes into the fetal blood, through the umbilical cord and to the placenta, where it acts.”

Particularly interesting is what their findings reveal about the tussle taking place in the womb.

In mice, the response to IGF2 in the blood vessels of the placenta is mediated by another protein, called IGF2R. ̽��ֱ��two genes that produce IGF2 and IGF2R are ‘imprinted’ – a process by which molecular switches on the genes identify their parental origin and can turn the genes on or off. In this case, only the copy of the igf2 gene inherited from the father is active, while only the copy of igf2r inherited from the mother is active.

Lead author Dr Miguel Constância, said: “One theory about imprinted genes is that paternally-expressed genes are greedy and selfish. They want to extract the most resources as possible from the mother. But maternally-expressed genes act as countermeasures to balance these demands.”

“In our study, the father’s gene drives the fetus’s demands for larger blood vessels and more nutrients, while the mother’s gene in the placenta tries to control how much nourishment she provides. There’s a tug-of-war taking place, a battle of the sexes at the level of the genome.”

̽��ֱ��team say their findings will allow a better understanding of how the fetus, placenta and mother communicate with each other during pregnancy. This in turn could lead to ways of measuring levels of IGF2 in the fetus and finding ways to use medication to normalise these levels or promote normal development of placental vasculature.

̽��ֱ��researchers used mice, as it is possible to manipulate their genes to mimic different developmental conditions. This enables them to study in detail the different mechanisms taking place. ̽��ֱ��physiology and biology of mice have many similarities with those of humans, allowing researchers to model human pregnancy, in order to understand it better.

̽��ֱ��lead researchers are based at the Department of Obstetrics and Gynaecology, the Medical Research Council Metabolic Diseases Unit, part of the Wellcome-MRC Institute of Metabolic Science, and the Centre for Trophoblast Research, all at the ̽��ֱ�� of Cambridge.

̽��ֱ��research was largely funded by the Biotechnology and Biological Sciences Research Council, Medical Research Council, Wellcome Trust and Centre for Trophoblast Research.

Reference
Sandovici, I et al. ̽��ֱ��Imprinted Igf2-Igf2r Axis is Critical for Matching Placental Microvasculature Expansion to Fetal Growth. Developmental Cell; 10 Jan 2022: DOI: 10.1016/j.devcel.2021.12.005

Cambridge scientists have identified a key signal that the fetus uses to control its supply of nutrients from the placenta in a tug-of-war between genes inherited from the father and from the mother. ̽��ֱ��study, carried out in mice, could help explain why some babies grow poorly in the womb.

̽��ֱ��father’s gene drives the fetus’s demands for larger blood vessels and more nutrients, while the mother’s gene in the placenta tries to control how much nourishment she provides

Miguel Constância

Ionel Sandovici

Section of mouse fetus and placenta

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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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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