Imprinted genes as master regulators of placental hormones

印记基因作为胎盘激素的主要调节因子

• 批准号: BB/V014765/1
• 负责人: Rosalind John
• 金额: $ 81.7万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV014765%2F1
• 关键词: Imprinted; genes; master; regulators; placental

Pregnancy is an extraordinary life-changing event full of physical and emotional changes to the mother. There are changes to maternal metabolism and the immune system required to support fetal growth and prevent fetal rejection. Considerable changes take place in the maternal brain preparing the mother for her new role in caring for her infant. All these changes require hormones produced by, or dependent on, the placenta. Ensuring normal placental development is therefore fundamentally important for the health of both the mother and her children.We are studying the development of cells in the placenta that manufacture placental hormones (endocrine cells). Specifically, we are interested in understanding how the number of endocrine cells is regulated by a family of genes called imprinted genes. Unlike most genes in mammals which are expressed from two copies, imprinted genes are expressed from one copy. This "monoallelic" expression is controlled by marks that are added to the genes called epigenetic marks. We do not fully understand why it is important for some genes in mammals to be expressed from only one copy but we do know that monoallelic expression makes imprinted genes highly vulnerable to mutation. A single genetic mutation can result in loss-of-function while exposure to prenatal adversity can alter epigenetic marks resulting in changes in the expression of imprinted genes.We have been studying the function of imprinted genes in placental development using mouse models. We discovered that maternally-expressed genes act to limit the number of endocrine cells in the placenta while paternally-expressed genes seem to have the opposite function. When the placenta has too few endocrine cells, expression of placental hormones is lower than normal and the fetus does not grow properly resulting in low birth weight. Mothers in these pregnancies also nurture their pups less. Both low birth weight and reduced maternal nurturing have been linked to adverse behavioural outcomes and we recently found that offspring from these pregnancies behave abnormally. These data highlight the importance of normal expression of these imprinted genes in the placenta for health in pregnancy and later in life, at least in mice.Here we will ask how imprinted genes work together to ensure that precisely the right number of cells develop for the optimal production of placental hormones. We will examine placenta with single or combined loss-of-function of the maternally-expressed Phlda2 gene and the paternally-expressed Peg3 gene to determine how many cells are present that express placental hormones. We will examine maternal serum to determine how these placental alterations alter hormones in the mother's blood. We will isolate single cells from the stem cell region of the placenta to identify and characterise progenitors for the endocrine lineages, and the impact of gene changes on their number and nature. We will use mouse trophoblast stem cells to establish the earliest consequence of these same modifications for development in culture and in chimeras. To translate our findings from mouse to human, we will modify the expression of PHLDA2 and PEG3 in human trophoblast stem cells to directly ask whether these genes regulate the development of placental endocrine lineages in humans. We will also ask whether there is a correlation between their expression and the composition of the placenta at term and the levels of serum placental lactogen using human placental samples we have already collected. In this way, we will establish whether these imprinted genes function antagonistically to regulate development of the placental endocrine lineages in both mice and human pregnancies. Through this greater understanding of placental development, our work will support optimal fetal growth and maternal wellbeing to improve lifelong health.

怀孕是一个非凡的改变生活的事件充满了身体和情感的变化给母亲。母体代谢和免疫系统发生变化，以支持胎儿生长和防止胎儿排斥。母亲的大脑发生了相当大的变化，使母亲为照顾婴儿的新角色做好准备。所有这些变化都需要胎盘产生或依赖于胎盘的激素。因此，确保胎盘的正常发育对母亲和孩子的健康至关重要。我们正在研究胎盘中产生胎盘激素的细胞（内分泌细胞）的发育。具体来说，我们感兴趣的是了解内分泌细胞的数量是如何被称为印记基因的基因家族调节的。与哺乳动物中大多数基因由两个拷贝表达不同，印记基因由一个拷贝表达。这种“单等位基因”表达是由添加到基因上的标记控制的，称为表观遗传标记。我们并不完全理解为什么哺乳动物中的某些基因只从一个拷贝表达是重要的，但我们知道单等位基因表达使印记基因非常容易突变。单一基因突变可导致功能丧失，而产前逆境可改变表观遗传标记，导致印记基因表达的变化。我们一直在使用小鼠模型研究印记基因在胎盘发育中的功能。我们发现母体表达的基因限制胎盘中内分泌细胞的数量，而父亲表达的基因似乎具有相反的功能。当胎盘内分泌细胞过少时，胎盘激素的表达低于正常水平，胎儿不能正常生长，导致出生体重低。这些怀孕中的母亲也较少养育他们的幼崽。出生体重低和母亲养育减少都与不良行为结果有关，我们最近发现这些怀孕的后代行为异常。这些数据强调了这些印记基因在胎盘中的正常表达对怀孕和以后生活中的健康的重要性，至少在小鼠中是这样。在这里，我们将询问印记基因如何共同工作，以确保精确的细胞数量发育，以最佳地产生胎盘激素。我们将检查胎盘与单一或组合的功能丧失的母亲表达的Phlda2基因和父亲表达的Peg3基因，以确定有多少细胞表达胎盘激素。我们将检查母体血清，以确定这些胎盘变化如何改变母亲血液中的激素。我们将从胎盘的干细胞区域分离单个细胞，以鉴定和鉴定内分泌谱系的祖细胞，以及基因变化对其数量和性质的影响。我们将使用小鼠滋养层干细胞来确定这些相同修饰在培养物和嵌合体中发育的最早结果。为了将我们的发现从小鼠转化为人类，我们将修改人类滋养层干细胞中PHLDA 2和PEG 3的表达，以直接询问这些基因是否调节人类胎盘内分泌谱系的发育。我们还将询问它们的表达与足月胎盘的组成以及我们已经收集的人胎盘样本的血清胎盘催乳素水平之间是否存在相关性。通过这种方式，我们将确定这些印记基因是否拮抗性地调节小鼠和人类妊娠中胎盘内分泌谱系的发育。通过对胎盘发育的更深入了解，我们的工作将支持最佳的胎儿生长和孕产妇健康，以改善终身健康。

项目成果

Epigenetic Epidemiology

表观遗传流行病学

• DOI: 10.1007/978-3-030-94475-9_8
• 发表时间: 2022
• 作者: John R