Ionel Sandovici - Academia.edu (original) (raw)

Papers by Ionel Sandovici

Expression microarray data obtained in rat pancreatic islets isolated at three months of age (3M ... more Expression microarray data obtained in rat pancreatic islets isolated at three months of age (3M - six samples) and 15 months of age (15M - 4 samples). Array profiling was performed using the RatRef-12 Expression BeadChips. The file is in Excel format with column 1 showing probe ID, and following columns showing raw data (one sample/column).

Frontiers in Endocrinology, 2021

BackgroundObesity is a major risk factor for dysglycemic disorders, including type 2 diabetes (T2... more BackgroundObesity is a major risk factor for dysglycemic disorders, including type 2 diabetes (T2D). However, there is wide phenotypic variation in metabolic profiles. Tissue-specific epigenetic modifications could be partially accountable for the observed phenotypic variability.ScopeThe aim of this systematic review was to summarize the available data on epigenetic signatures in human adipose tissue (AT) that characterize overweight or obesity-related insulin resistance (IR) and dysglycemia states and to identify potential underlying mechanisms through the use of unbiased bioinformatics approaches.MethodsOriginal data published in the last decade concerning the comparison of epigenetic marks in human AT of individuals with metabolically unhealthy overweight/obesity (MUHO) versus normal weight individuals or individuals with metabolically healthy overweight/obesity (MHO) was assessed. Furthermore, association of these epigenetic marks with IR/dysglycemic traits, including T2D, was c...

Genes, 2021

Genomic imprinting, an epigenetic phenomenon that causes the expression of a small set of genes i... more Genomic imprinting, an epigenetic phenomenon that causes the expression of a small set of genes in a parent-of-origin-specific manner, is thought to have co-evolved with placentation. Many imprinted genes are expressed in the placenta, where they play diverse roles related to development and nutrient supply function. However, only a small number of imprinted genes have been functionally tested for a role in nutrient transfer capacity in relation to the structural characteristics of the exchange labyrinthine zone. Here, we examine the transfer capacity in a mouse model deficient for the maternally expressed Phlda2 gene, which results in placental overgrowth and a transient reduction in fetal growth. Using stereology, we show that the morphology of the labyrinthine zone in Phlda2−/+ mutants is normal at E16 and E19. In vivo placental transfer of radiolabeled solutes 14C-methyl-D-glucose and 14C-MeAIB remains unaffected at both gestational time points. However, placental passive permea...

Scientific Reports, 2021

When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive chang... more When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit h...

Yearbook of Paediatric Endocrinology, 2021

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Impri... more The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, 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 any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Here ... more 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 m...

American Journal of Physiology-Endocrinology and Metabolism, 2019

Antenatal stress increases the prevalence of diseases in later life, which shows a strong sex-spe... more Antenatal stress increases the prevalence of diseases in later life, which shows a strong sex-specific effect. However, the underlying mechanisms remain unknown. Maternal glucocorticoids can be elevated by stress and are potential candidates to mediate the effects of stress on the offspring sex-specifically. A comprehensive evaluation of dynamic maternal and placental mechanisms modulating fetal glucocorticoid exposure upon maternal stress was long overdue. Here, we addressed this gap in knowledge by investigating sex-specific responses to midgestational stress in mice. We observed increased levels of maternal corticosterone, the main glucocorticoid in rodents, along with higher corticosteroid-binding globulin levels at midgestation in C57Bl/6 dams exposed to sound stress. This resulted in elevated corticosterone in female fetuses, whereas male offspring were unaffected. We identified that increased placental expression of the glucocorticoid-inactivating enzyme 11β-hydroxysteroid de...

SUMMARYIn all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but... more SUMMARYIn 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 ...

Previous studies suggest that the placental supply of nutrients to the fetus adapts according to ... more 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 p110α impairs feto-placental growth but placental nutrient supply is adaptively increased. Here we explore the role of p110α 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 p110α either by ~50% or ~100% in the fetal lineages and/or trophoblast, this study shows that p110α in the fetus is essential for prenatal development and a major regulator of placental phenotype in mice. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of t...

Scientific reports, 2017

Endocrine-disrupting chemicals such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), ... more Endocrine-disrupting chemicals such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), are bioaccumulated in the adipose tissue (AT) and have been implicated in the obesity and diabetes epidemic. Thus, it is hypothesized that p,p'-DDE exposure could aggravate the harm of an obesogenic context. We explored the effects of 12 weeks exposure in male Wistar rats' metabolism and AT biology, assessing a range of metabolic, biochemical and histological parameters. p,p'-DDE -treatment exacerbated several of the metabolic syndrome-accompanying features induced by high-fat diet (HF), such as dyslipidaemia, glucose intolerance and hypertension. A transcriptome analysis comparing mesenteric visceral AT (vAT) of HF and HF/DDE groups revealed a decrease in expression of nervous system and tissue development-related genes, with special relevance for the neuropeptide galanin that also revealed DNA methylation changes at its promoter region. Additionally, we observed an increase...

The Journal of Physiology, 2017

Bloomfield FH, van Zijl PL, Bauer MK & Harding JE. (2002b). A chronic low dose infusion of insuli... more Bloomfield FH, van Zijl PL, Bauer MK & Harding JE. (2002b). A chronic low dose infusion of insulin-like growth factor I alters placental function but does not affect fetal growth. Reprodroduction, Fertility and Develpoment 14, 393-400. Bloxam DL, Bax BE & Bax CM. (1994). Epidermal growth factor and insulin-like growth factor I differently influence the directional accumulation and transfer of 2-aminoisobutyrate (AIB) by human placental trophoblast in two-sided culture. Biochemical and Biophysical Research Communications 199, 922-929.

Aging, 2011

We have recently demonstrated that exposure to a suboptimal diet during early development leads t... more We have recently demonstrated that exposure to a suboptimal diet during early development leads to abnormal epigenetic regulation of a promoter-enhancer interaction at the gene encoding HNF-4α, a key transcription factor required for pancreatic β-cell differentiation and glucose homeostasis. In addition, our studies revealed that the suboptimal maternal diet amplifies the age-associated epigenetic silencing of this locus. In this research perspective we discuss these novel findings in the context of the growing list of epigenetic mechanisms by which the environment can affect gene activity and emphasize their implications for the understanding of the mechanistic basis of the development of type 2 diabetes with age.

The Journal of Physiology, 2008

The Guide to Investigation of Mouse Pregnancy, 2014

Chapter Summary In mammals, a small number of genes are expressed in a parental origin–specific m... more Chapter Summary In mammals, a small number of genes are expressed in a parental origin–specific manner. These so-called imprinted genes are marked by parent-specific epigenetic modifications during germline development. The gametic imprints are maintained after fertilization when the (epi)genome is extensively reprogrammed. Many imprinted genes reside in clusters, regulated by noncoding RNAs and CCCTC-binding factor-dependent insulators. Of the ∼150 imprinted genes identified in the mouse, many undergo tissue-specific imprinting, and a significant number are imprinted exclusively in the placenta. Imprinting is hypothesized to have evolved as a mechanism to balance parental resource allocation. Several imprinted genes have a demonstrated role in the control of placental supply of and fetal demand for maternal nutrients and hence growth control. In this chapter, we discuss the contribution of genomic imprinting to the physiology and function of the placenta and to the allocation of maternal resources during pregnancy.

The Guide to Investigation of Mouse Pregnancy, 2014

Chapter Summary Imprinted genes exhibit parental-specific monoallelic expression; associated hall... more Chapter Summary Imprinted genes exhibit parental-specific monoallelic expression; associated hallmarks include differential DNA methylation and histone modifications at promoters and imprinted control regions. This chapter summarizes protocols for the analysis of monoallelic gene expression, DNA methylation, and histone modifications of imprinted genes, and highlights several aspects that are critical when working with mouse placental samples.

Reproductive BioMedicine Online, 2012

He was trained in the laboratories of Carmen Sapienza (Temple University, Philadelphia) and Migue... more He was trained in the laboratories of Carmen Sapienza (Temple University, Philadelphia) and Miguel Constância and Wolf Reik (Babraham Institute, Cambridge). He is now a research associate in the laboratory of Miguel Constância at the University of Cambridge, where he studies the role of Igf2 in placental and pancreatic development, as well as the links between environment and epigenetic regulation of gene activity.

Cardiovascular research, Jan 5, 2015

The strategies that control formation of the ventricular wall during heart development are not we... more The strategies that control formation of the ventricular wall during heart development are not well understood. In previous studies, we documented IGF2 as a major mitogenic signal that controls ventricular cardiomyocyte proliferation and chamber wall expansion. Our objective in this study was to define the tissue source of IGF2 in heart development and the upstream pathways that control its expression. Using a number of mouse genetic tools, we confirm that the critical source of IGF2 is the epicardium. We find that epicardial Igf2 expression is controlled in a biphasic manner, first induced by erythropoietin, and then regulated by oxygen and glucose with onset of placental function. Both processes are independently controlled by retinoic acid signaling. Our results demonstrate that ventricular wall cardiomyocyte proliferation is subdivided into distinct regulatory phases. Each involves instructive cues that originate outside the heart and thereby act on the epicardium in an endocrin...

The FASEB Journal, 2011

The healthy development of the fetus depends on an optimal balance between fetal genetic drive fo... more The healthy development of the fetus depends on an optimal balance between fetal genetic drive for growth and the maternal ability to provide nutrients through the placenta. Nothing is known about fetalplacental signaling in response to increased fetal demand in the situation of overgrowth. Here, we examined this question using the H19 ⌬13 mouse model, shown previously to result in elevated levels of Igf2. Fetal and placental weights in H19 ⌬13 were increased by 23% and 45%, respectively, at E19, when compared with wild-type mice. Unexpectedly, we found that disproportionately large H19 ⌬13 placentas transport 20-35% less (per gram placenta) glucose and system A amino acids and have similar reductions in passive permeability, despite a significantly greater surface area for nutrient exchange and theoretical diffusion capacity compared with wild-type mice. Expression of key transporter genes Slc2a3 and Slc38a4 was reduced by ϳ20%. Decreasing the overgrowth of the H19 ⌬13 placenta by genetically reducing levels of Igf2P0 resulted in up-regulation of system A activity and maintenance of fetal overgrowth. Our results provide direct evidence that large placentas can modify their nutrient transfer capacity to regulate fetal nutrient acquisition. Our findings are indicative of fetal-placental signaling mechanisms that limit total demand for maternal nutrients.-Angiolini, E.

Expression microarray data obtained in rat pancreatic islets isolated at three months of age (3M ... more Expression microarray data obtained in rat pancreatic islets isolated at three months of age (3M - six samples) and 15 months of age (15M - 4 samples). Array profiling was performed using the RatRef-12 Expression BeadChips. The file is in Excel format with column 1 showing probe ID, and following columns showing raw data (one sample/column).

Frontiers in Endocrinology, 2021

BackgroundObesity is a major risk factor for dysglycemic disorders, including type 2 diabetes (T2... more BackgroundObesity is a major risk factor for dysglycemic disorders, including type 2 diabetes (T2D). However, there is wide phenotypic variation in metabolic profiles. Tissue-specific epigenetic modifications could be partially accountable for the observed phenotypic variability.ScopeThe aim of this systematic review was to summarize the available data on epigenetic signatures in human adipose tissue (AT) that characterize overweight or obesity-related insulin resistance (IR) and dysglycemia states and to identify potential underlying mechanisms through the use of unbiased bioinformatics approaches.MethodsOriginal data published in the last decade concerning the comparison of epigenetic marks in human AT of individuals with metabolically unhealthy overweight/obesity (MUHO) versus normal weight individuals or individuals with metabolically healthy overweight/obesity (MHO) was assessed. Furthermore, association of these epigenetic marks with IR/dysglycemic traits, including T2D, was c...

Genes, 2021

Genomic imprinting, an epigenetic phenomenon that causes the expression of a small set of genes i... more Genomic imprinting, an epigenetic phenomenon that causes the expression of a small set of genes in a parent-of-origin-specific manner, is thought to have co-evolved with placentation. Many imprinted genes are expressed in the placenta, where they play diverse roles related to development and nutrient supply function. However, only a small number of imprinted genes have been functionally tested for a role in nutrient transfer capacity in relation to the structural characteristics of the exchange labyrinthine zone. Here, we examine the transfer capacity in a mouse model deficient for the maternally expressed Phlda2 gene, which results in placental overgrowth and a transient reduction in fetal growth. Using stereology, we show that the morphology of the labyrinthine zone in Phlda2−/+ mutants is normal at E16 and E19. In vivo placental transfer of radiolabeled solutes 14C-methyl-D-glucose and 14C-MeAIB remains unaffected at both gestational time points. However, placental passive permea...

Scientific Reports, 2021

When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive chang... more When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit h...

Yearbook of Paediatric Endocrinology, 2021

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Impri... more The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, 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 any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Here ... more 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 m...

American Journal of Physiology-Endocrinology and Metabolism, 2019

Antenatal stress increases the prevalence of diseases in later life, which shows a strong sex-spe... more Antenatal stress increases the prevalence of diseases in later life, which shows a strong sex-specific effect. However, the underlying mechanisms remain unknown. Maternal glucocorticoids can be elevated by stress and are potential candidates to mediate the effects of stress on the offspring sex-specifically. A comprehensive evaluation of dynamic maternal and placental mechanisms modulating fetal glucocorticoid exposure upon maternal stress was long overdue. Here, we addressed this gap in knowledge by investigating sex-specific responses to midgestational stress in mice. We observed increased levels of maternal corticosterone, the main glucocorticoid in rodents, along with higher corticosteroid-binding globulin levels at midgestation in C57Bl/6 dams exposed to sound stress. This resulted in elevated corticosterone in female fetuses, whereas male offspring were unaffected. We identified that increased placental expression of the glucocorticoid-inactivating enzyme 11β-hydroxysteroid de...

SUMMARYIn all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but... more SUMMARYIn 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 ...

Previous studies suggest that the placental supply of nutrients to the fetus adapts according to ... more 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 p110α impairs feto-placental growth but placental nutrient supply is adaptively increased. Here we explore the role of p110α 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 p110α either by ~50% or ~100% in the fetal lineages and/or trophoblast, this study shows that p110α in the fetus is essential for prenatal development and a major regulator of placental phenotype in mice. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of t...

Scientific reports, 2017

Endocrine-disrupting chemicals such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), ... more Endocrine-disrupting chemicals such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), are bioaccumulated in the adipose tissue (AT) and have been implicated in the obesity and diabetes epidemic. Thus, it is hypothesized that p,p'-DDE exposure could aggravate the harm of an obesogenic context. We explored the effects of 12 weeks exposure in male Wistar rats' metabolism and AT biology, assessing a range of metabolic, biochemical and histological parameters. p,p'-DDE -treatment exacerbated several of the metabolic syndrome-accompanying features induced by high-fat diet (HF), such as dyslipidaemia, glucose intolerance and hypertension. A transcriptome analysis comparing mesenteric visceral AT (vAT) of HF and HF/DDE groups revealed a decrease in expression of nervous system and tissue development-related genes, with special relevance for the neuropeptide galanin that also revealed DNA methylation changes at its promoter region. Additionally, we observed an increase...

The Journal of Physiology, 2017

Bloomfield FH, van Zijl PL, Bauer MK & Harding JE. (2002b). A chronic low dose infusion of insuli... more Bloomfield FH, van Zijl PL, Bauer MK & Harding JE. (2002b). A chronic low dose infusion of insulin-like growth factor I alters placental function but does not affect fetal growth. Reprodroduction, Fertility and Develpoment 14, 393-400. Bloxam DL, Bax BE & Bax CM. (1994). Epidermal growth factor and insulin-like growth factor I differently influence the directional accumulation and transfer of 2-aminoisobutyrate (AIB) by human placental trophoblast in two-sided culture. Biochemical and Biophysical Research Communications 199, 922-929.

Aging, 2011

We have recently demonstrated that exposure to a suboptimal diet during early development leads t... more We have recently demonstrated that exposure to a suboptimal diet during early development leads to abnormal epigenetic regulation of a promoter-enhancer interaction at the gene encoding HNF-4α, a key transcription factor required for pancreatic β-cell differentiation and glucose homeostasis. In addition, our studies revealed that the suboptimal maternal diet amplifies the age-associated epigenetic silencing of this locus. In this research perspective we discuss these novel findings in the context of the growing list of epigenetic mechanisms by which the environment can affect gene activity and emphasize their implications for the understanding of the mechanistic basis of the development of type 2 diabetes with age.

The Journal of Physiology, 2008

The Guide to Investigation of Mouse Pregnancy, 2014

Chapter Summary In mammals, a small number of genes are expressed in a parental origin–specific m... more Chapter Summary In mammals, a small number of genes are expressed in a parental origin–specific manner. These so-called imprinted genes are marked by parent-specific epigenetic modifications during germline development. The gametic imprints are maintained after fertilization when the (epi)genome is extensively reprogrammed. Many imprinted genes reside in clusters, regulated by noncoding RNAs and CCCTC-binding factor-dependent insulators. Of the ∼150 imprinted genes identified in the mouse, many undergo tissue-specific imprinting, and a significant number are imprinted exclusively in the placenta. Imprinting is hypothesized to have evolved as a mechanism to balance parental resource allocation. Several imprinted genes have a demonstrated role in the control of placental supply of and fetal demand for maternal nutrients and hence growth control. In this chapter, we discuss the contribution of genomic imprinting to the physiology and function of the placenta and to the allocation of maternal resources during pregnancy.

The Guide to Investigation of Mouse Pregnancy, 2014

Chapter Summary Imprinted genes exhibit parental-specific monoallelic expression; associated hall... more Chapter Summary Imprinted genes exhibit parental-specific monoallelic expression; associated hallmarks include differential DNA methylation and histone modifications at promoters and imprinted control regions. This chapter summarizes protocols for the analysis of monoallelic gene expression, DNA methylation, and histone modifications of imprinted genes, and highlights several aspects that are critical when working with mouse placental samples.

Reproductive BioMedicine Online, 2012

He was trained in the laboratories of Carmen Sapienza (Temple University, Philadelphia) and Migue... more He was trained in the laboratories of Carmen Sapienza (Temple University, Philadelphia) and Miguel Constância and Wolf Reik (Babraham Institute, Cambridge). He is now a research associate in the laboratory of Miguel Constância at the University of Cambridge, where he studies the role of Igf2 in placental and pancreatic development, as well as the links between environment and epigenetic regulation of gene activity.

Cardiovascular research, Jan 5, 2015

The strategies that control formation of the ventricular wall during heart development are not we... more The strategies that control formation of the ventricular wall during heart development are not well understood. In previous studies, we documented IGF2 as a major mitogenic signal that controls ventricular cardiomyocyte proliferation and chamber wall expansion. Our objective in this study was to define the tissue source of IGF2 in heart development and the upstream pathways that control its expression. Using a number of mouse genetic tools, we confirm that the critical source of IGF2 is the epicardium. We find that epicardial Igf2 expression is controlled in a biphasic manner, first induced by erythropoietin, and then regulated by oxygen and glucose with onset of placental function. Both processes are independently controlled by retinoic acid signaling. Our results demonstrate that ventricular wall cardiomyocyte proliferation is subdivided into distinct regulatory phases. Each involves instructive cues that originate outside the heart and thereby act on the epicardium in an endocrin...

The FASEB Journal, 2011

The healthy development of the fetus depends on an optimal balance between fetal genetic drive fo... more The healthy development of the fetus depends on an optimal balance between fetal genetic drive for growth and the maternal ability to provide nutrients through the placenta. Nothing is known about fetalplacental signaling in response to increased fetal demand in the situation of overgrowth. Here, we examined this question using the H19 ⌬13 mouse model, shown previously to result in elevated levels of Igf2. Fetal and placental weights in H19 ⌬13 were increased by 23% and 45%, respectively, at E19, when compared with wild-type mice. Unexpectedly, we found that disproportionately large H19 ⌬13 placentas transport 20-35% less (per gram placenta) glucose and system A amino acids and have similar reductions in passive permeability, despite a significantly greater surface area for nutrient exchange and theoretical diffusion capacity compared with wild-type mice. Expression of key transporter genes Slc2a3 and Slc38a4 was reduced by ϳ20%. Decreasing the overgrowth of the H19 ⌬13 placenta by genetically reducing levels of Igf2P0 resulted in up-regulation of system A activity and maintenance of fetal overgrowth. Our results provide direct evidence that large placentas can modify their nutrient transfer capacity to regulate fetal nutrient acquisition. Our findings are indicative of fetal-placental signaling mechanisms that limit total demand for maternal nutrients.-Angiolini, E.