Biology subjects

Constancia, M.

Publications and source records attributed to Constancia, M..

6 recordsLinked to original sources

bioRxiv2023

Genome-wide analysis of promoter contacts identifies novel regulators of late-stage adipogenesis

Adipogenesis is a multi-stage process essential for healthy fat storage and metabolic regulation. While early regulatory mechanisms are well characterized, the control of late-stage adipocyte differentiation remains poorly understood. Integrating CAGE-seq, promoter capture Hi-C, and a high-throughput siRNA screen of druggable genes, we report here that chromatin architecture rewiring promotes gene regulation changes essential for terminal adipogenesis. We identified nine clusters of dynamic promoter-anchored chromosomal interactions, many involving distal enhancers. Functional screening of genes engaged in these interactions revealed 19 novel regulators of late adipogenesis, including proteins with peptidase and ubiquitin ligase activity. Human genetic variant-to-gene mapping, coupled with cross-species chromatin interaction and synteny analyses, highlighted new gene-trait associations relevant to lipid traits (FXYD5, LAP3, SGPP1) and type 2 diabetes (FBXO17, FN3KRP, ZFAND6, TTC3). Our findings define the 3D gene regulatory landscape of late adipogenesis. The molecular links uncovered here provide mechanistic insight into metabolic disease risk and potential interventions.

genetics↗

bioRxiv2023

Fetal manipulation of maternal metabolism is a critical function of Igf2 imprinting

Maternal-offspring interactions in mammals are mainly characterised by cooperation, but also conflict. Over evolutionary time, the fetus has evolved to manipulate the mothers physiology to increase nutrient transfer through the placenta, but these mechanisms are poorly characterized. The imprinted Igf2 (insulin-like growth factor 2) gene is highly expressed in mouse placental cells with endocrine functions. Here, we show that in the mouse, deletion of Igf2 in these cells leads to impaired placental endocrine signalling to the mother, but remarkably does not result in changes in placental morphology, growth or size. Mechanistically, we find that Igf2 via defective production of hormones, including prolactins, is essential for the establishment of the insulin-resistance state during pregnancy, and the appropriate partitioning of nutrients to the developing fetus. Consequently, fetuses are growth restricted and hypoglycemic, due to impaired placental glucose transfer from the mother to the fetus. Furthermore, Igf2 loss from placental endocrine cells has long-lasting effects on offspring adiposity and glucose homeostasis in adult life. Our study provides long-sought compelling experimental evidence for an intrinsic fetal manipulation system, which operates in the placenta to modify maternal metabolism and resource allocation to the fetus, with consequences for offspring metabolic health in later life.

developmental biology↗

bioRxiv2022

The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Here, we uncover the control mechanisms and physiological functions of Mir483 in vivo, by generating constitutive loss-of-function and over-expressing mice. Mir483 expression is imprinted and dependent on the Igf2 promoters and Igf2/H19 imprinting control region. Over-expression of Mir483 causes severe mid-gestation fetal, but not placental, growth restriction, and late lethality. Fetal death is prevented by restoring Mir483 to endogenous levels using an inducible transgenic system. Continuous postnatal Mir483 over-expression induces growth stunting, elevated hepatic lipid content, increased adiposity, reduced local and systemic IGF1 levels and increased GH. The growth phenotypes are rescued by IGF1 infusion. Our findings provide evidence for a novel functional antagonism between a growth-suppressor microRNA and its growth-promoter host gene, and suggest that Mir483 evolved to limit excessive tissue growth through repression of IGF ligand signalling.

developmental biology↗

bioRxiv2019

Mesenchymal Igf2 is a major paracrine regulator of pancreatic growth and function

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Here we demonstrate that many imprinted genes are highly expressed in the pancreatic mesenchyme, and explore the role of Igf2 in-vivo. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy. Surprisingly, mesenchymal mass is unaffected, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Furthermore, increased IGF2 activity specifically in the mesenchyme, through Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Ex-vivo exposure of primary acinar cells to exogenous IGF2 increases cell proliferation and amylase production through AKT signalling. We propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.

developmental biology↗

bioRxiv2019

Fetus-derived IGF2 matches placental development to fetal demand

In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here we demonstrate, through fetal, endothelial, hematopoietic and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signalling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.

developmental biology↗

bioRxiv2018

Fetal and trophoblast PI3Kp110α have distinct roles in regulating resource supply to the growing fetus

Previous studies suggest that the placental supply of nutrients to the fetus adapts according to fetal demand. However, the signaling events underlying placental adaptations remain largely unknown. Earlier work in mice has revealed that loss of the phosphoinositide 3-kinase p110 impairs feto-placental growth but placental nutrient supply is adaptively increased. Here we explore the role of p110 in the epiblast-derived (fetal) and trophoblast lineages of the conceptus in relation to feto-placental growth and placental development and transfer function. Using conditional gene manipulations to knock-down p110 either by [~]50% or [~]100% in the fetal lineages and/or trophoblast, this study shows that p110 in the fetus is essential for prenatal development and a major regulator of placental phenotype in mice. Complete loss of fetal p110 caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110 also resulted in abnormal placental development, although fetuses were viable. However, in response to complete loss of trophoblast p110, the placenta failed to transport sufficient amino acid to match fetal demands for growth. Using RNA-seq, we identified several genes downstream of p110 in the trophoblast that are important in adapting placental phenotype to support fetal growth. Further work using CRISPR/Cas9 genome targeting showed that loss of p110 differentially affects the expression of genes in trophoblast and embryonic stem cells. Our findings thus reveal important, but distinct roles for p110 signaling in the different compartments of the conceptus, which control fetal resource acquisition and ultimately affect healthy growth.\n\nOne Sentence SummaryFetal and trophoblast p110 modify resource allocation

developmental biology↗