Dynamic expression of TET1, TET2, and TET3 dioxygenases in mouse and human placentas throughout gestation

Rakoczy, Joanna; Padmanabhan, Nisha; Krzak, Ada Maria; Kieckbusch, Jens; Cindrová‐Davies, Tereza; Watson, Erica D.

doi:10.1016/j.placenta.2017.09.008

Cited by 21 publications

(20 citation statements)

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“…The observed upregulation is in disagreement with previous results by Wu and collaborators [36] in which they observed downregulation of all TET enzymes in villous tissue from early pregnancy loss cases, however, this study was carried out between 6-8 weeks of gestation which might explain the discrepancies observed. Indeed, Rakoczy and collaborators showed a specific cellular localization for the different TET enzymes in human placentas, suggesting a dynamic role in the regulation of transcriptional activity of trophoblast progenitors and differentiated cell subtypes [15]. In our study, despite TET2 and TET3 being upregulated in idiopathic SA placentas, we did not observe significant changes in DNA hydroxymethylation global levels.…”

Section: Discussioncontrasting

confidence: 51%

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Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

et al. 2019

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Epigenetic mechanisms such as genomic imprinting have a fundamental role in embryo and fetal development. Hence, we here studied expression levels of epigenetic modifiers and imprinted genes in cases of ididopathic spontaneous abortion (SA). Thirty-five placental samples and 35 matched fetal tissues from second trimester SA were analysed; including 16 controls (placental and fetal infections as the known cause of spontaneous abortion) and 19 idiopathic SA cases. Transcript levels of epigenetic regulators and imprinted genes were measured by qRT-PCR and methylation at imprinted genes was studied by bisulfite genomic sequencing and MS-MLPA. Global DNA hydroxymethylation (5-hmC) levels were measured by an ELISA-based assay. We observed an upregulation of TET2 and TET3 in placental samples from idiopathic SA cases; however, no significant difference in global 5-hmC levels was observed. On the contrary, in fetal tissues, TET3 was markedly downregulated in idiopathic SA, showing an opposite trend to that observed in placental tissue. IGF2 and CDKN1C were upregulated and MEST downregulated in placentas from idiopathic SA cases; concordantly, IGF2 was also upregulated in fetal tissues from idiopathic SA cases. Although not reaching statistical significance, an increase in methylation levels of MEST, KvDMR1 and H19 DMRs was observed in idiopathic SA cases, concordantly with the observed changes in expression. Our study reveals, for the first time, deregulation of epigenetic modifiers and imprinted genes in both placental and fetal tissues from idiopathic SA cases in the second trimester of pregnancy, indicating a critical role during pregnancy.

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Section: Discussioncontrasting

confidence: 51%

“…These enzymes can also further oxidize 5-hmC into 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC), a process thought to be involved in active DNA demethylation [13,14]. Like DNMTs, TETs are also involved in the differentiation and regulation of placental trophoblasts [15,16].…”

Section: Introductionmentioning

confidence: 99%

Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

et al. 2019

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“…In mice, TET3 affects epigenetic reprogramming in oocytes and zygotes, is required for neonatal growth, and depletion of TET3 in female mice results in reduced fecundity 49,50 . In humans, TET3 expression was detected in the villus cytotrophoblast cells in the first trimester as well as in maternal decidua of placentas 51 . Expression profiling showed elevated TET3 transcripts in preeclamptic placentas and in pregnancies ending with the birth of a newborn that is small for gestational age (SGA) 52 .…”

Section: Resultsmentioning

confidence: 99%

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

LaBella

Abraham

Pichkar

et al. 2019

Preprint

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35Human pregnancy requires the coordinated function of multiple tissues in both mother and fetus and has 36 evolved in concert with major human adaptations. As a result, pregnancy-associated phenotypes and 37 related disorders are genetically complex and have likely been sculpted by diverse evolutionary forces. 38 However, there is no framework to comprehensively evaluate how these traits evolved or to explore the 39 relationship of evolutionary signatures on trait-associated genetic variants to molecular function. Here we 40develop an approach to test for signatures of diverse evolutionary forces, including multiple types of 41 selection, and apply it to genomic regions associated with spontaneous preterm birth (sPTB), a complex 42 disorder of global health concern. We find that sPTB-associated regions harbor diverse evolutionary 43 signatures including evolutionary sequence conservation (consistent with the action of negative selection), 44 excess population differentiation (local adaptation), accelerated evolution (positive selection), and 45 balanced polymorphism (balancing selection). Furthermore, these genomic regions show diverse 46 functional characteristics which enables us to use evolutionary and molecular lines of evidence to develop 47 54Mammalian pregnancy requires the coordination of multiple maternal and fetal tissues 1,2 and extensive 55 modulation of the maternal immune system so that the genetically distinct fetus is not immunologically 56 rejected 3 . Given this context, pregnancy-related phenotypes and disorders are likely to have experienced 57 diverse selective pressures. This is particularly likely on the human lineage where pregnancy has been 58 shaped by unique human adaptations such as bipedality and enlarged brain size 4-8 . One major disorder of 59 pregnancy is preterm birth (PTB), a complex multifactorial syndrome 9 that affects 10% of pregnancies in 60 the United States and more than 15 million pregnancies worldwide each year 10,11 . PTB leads to increased 61 infant mortality rates and significant short-and long-term morbidity [11][12][13][14] . Risk for PTB varies 62 substantially with race, environment, comorbidities, and genetic factors 15 . PTB is broadly classified into 63 iatrogenic PTB, when it is associated with medical conditions such as preeclampsia (PE) or intrauterine 64 growth restriction (IUGR), and spontaneous PTB (sPTB), which occurs in the absence of preexisting 65 medical conditions or is initiated by preterm premature rupture of membranes [16][17][18][19] . The biological 66 pathways contributing to sPTB remain poorly understood 9 , but diverse lines of evidence suggest that 67 maternal genetic variation is an important contributor 20-24 . 68The complexity of human pregnancy and association with unique human adaptations raise the hypothesis 69 that genetic variants associated with birth timing and sPTB have been shaped by diverse evolutionary 70 forces. Consistent with this hypothesis, several immune genes involved in pregnancy have signatures of 71 recent purifyin...

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“…A expressão das enzimas relacionadas com a reprogramação epigenética, especificamente relacionadas à metilação de DNA, já foi avaliada na placenta de camundongos (RAKOCZY et al, 2017), suínos (KO, Y.-G. et al, 2014) e humanos (HE, Z.-M. et al, 2014;ROBERTSON et al, 1999). Em bovinos, no entanto, ainda existe pouca informação na literatura sobre a expressão dessas enzimas em placenta, principalmente em placenta de bovinos clones.…”

Section: Discussionunclassified

“…Nesse trabalho os resultados mostraram maiores níveis de mRNA para TET1 nos clones, enquanto que TET2 foi maior nos controles (Figura 6). Extrapolando para outras espécies, esses achados podem estar relacionados com o papel dinâmico que essas enzimas desempenham na regulação da atividade transcricional na placenta de camundongos e humanos (RAKOCZY et al, 2017). Além disso, estudos recentes em humanos identificaram que a expressão de TET2 e TET3 são mais abundantes nas placentas comparados a outros tecidos (HERNANDEZ MORA et al, 2018).…”

Section: Discussionunclassified

Compreendendo o organizational misbehaviour na gestão pública: um estudo de caso em uma instituição de ensino superior pública

Gervásio¹

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Aos meus pais, Valéria e Wytergon, pelo apoio fundamental durante essa jornada e por não medirem esforços para realização dos meus sonhos. Obrigada por toda base e por entenderem minha distância. Á toda minha família, pelo incentivo, força e por sempre acreditarem em mim. Sem vocês nada disso seria possível. Ao meu orientador, Maurício, pela confiança, paciência e oportunidade de realização desse trabalho. Obrigada por todos os ensinamentos transmitidos e por contribuir de forma admirável para meu crescimento profissional. Ao meu namorado, Leo, pelo suporte e carinho durante todo tempo de realização desse trabalho. Aos meus amigos de longa data e aqueles que fiz em Brasília, obrigada pelos bons momentos vividos, amizade e disponibilidade em ajudar no que fosse preciso. A toda equipe do LRA, pela contribuição para minha formação e, sobretudo para a realização desse trabalho. Obrigada à Embrapa Recursos Genéticos e Biotecnologia por toda a estrutura e pela oportunidade de realizar este trabalho.

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Dynamic expression of TET1, TET2, and TET3 dioxygenases in mouse and human placentas throughout gestation

Abstract: Altogether, our data suggest that TET enzymes may play a dynamic role in the regulation of transcriptional activity of trophoblast progenitors and differentiated cell subtypes in mouse and human placentas.

Cited by 21 publications

References 58 publications

Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

Compreendendo o organizational misbehaviour na gestão pública: um estudo de caso em uma instituição de ensino superior pública

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