scholarly journals Early-life environment programs reproductive strategies through epigenetic regulation of SRD5A1

2020 ◽  
Author(s):  
Ben Bar-Sadeh ◽  
Or Eden ◽  
Lilach Pnueli ◽  
Kurshida Begum ◽  
Gregory Leeman ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Early Life ◽  
Reproductive Strategies ◽  
Life History Theory ◽  
Molecular Mechanisms ◽  
Reproductive Function ◽  
Transcriptional Enhancer ◽  
Pubertal Onset ◽  
Early Life Environment

AbstractReproductive function and duration of the reproductive life span are phenotypically plastic and programmed in response to the early-life environment. Such adaptive responses are described and rationalized in life history theory in the context of resource availability, but the molecular mechanisms responsible have remained enigmatic. In this study, we hypothesized that epigenetic modifications underlie adaptive reproductive strategies, and found distinct methylation patterns in buccal DNA of Bangladeshi women who grew up in Bangladesh or the UK. The later pubertal onset and lower ovarian reserve associated with Bangladeshi childhood was seen to correlate with more numerous childhood infections, so we adopted a mouse model of pre-pubertal colitis to mimic these conditions. These mice have a similarly-altered reproductive phenotype, which enabled us to determine its mechanistic basis. Several genes encoding proteins with known functions in follicle recruitment were differentially expressed in the mice ovaries, and were also differentially methylated in the women’s buccal DNA. One of these, SRD5A1 which encodes the steroidogenic enzyme 5α reductase-1, was down-regulated in the mice ovaries and hyper methylated at the same putative transcriptional enhancer as in the women’s DNA; the levels of methylation correlating with gene expression levels. Srd5a1 expression was down-regulated also in the hypothalamus where 5α reductase-1 catalyzes production of neurosteroids that regulate gonadotropin releasing hormone (GnRH). Chemical inhibition of this enzyme affected both GnRH synthesis and release, and resulted in delayed pubertal onset in vivo. The activity of 5α reductase-1 in hypothalamus and ovary and the sensitivity of SRD5A1 to epigenetic regulation attest to its role in directing long-term physiological strategies in response to environmental conditions. In the reproductive axis, this includes timing of pubertal onset, adult reproductive function and duration of the reproductive lifespan.

scholarly journals Functional in vivo characterization of zebrafish sox10 enhancers in melanoma and neural crest

2020 ◽  
Author(s):  
Rebecca L. Cunningham ◽  
Eva T. Kramer ◽  
Sophia K. DeGeorgia ◽  
Shayana Seneviratne ◽  
Vadim Grigura ◽  
...  
Keyword(s):  
Neural Crest ◽  
Epigenetic Regulation ◽  
High Specificity ◽  
Open Chromatin ◽  
Transcriptional Enhancer ◽  
Reporter Expression ◽  
Transgenic Lines ◽  
In Vivo Characterization

AbstractThe re-emergence of a neural crest transcriptional program, including Sox10 upregulation, is a key step in melanoma initiation in humans and zebrafish. We hypothesize that epigenetic regulation of sox10 modulates melanoma initiation. ATAC-Seq analysis of zebrafish melanoma tumors identifies recurrently open chromatin domains near sox10. Reporter constructs for each putative sox10 enhancer were examined in zebrafish embryos for neural crest activity and in stable transgenic lines for melanoma activity. One element, peak5 (23 kilobases upstream of sox10), drives EGFP reporter expression in a subset of neural crest cells, Kolmer-Agduhr neurons, and early melanoma patches and tumors with high specificity. A ∼200 bp region, conserved across the Cyprinidae family (fish), is required for peak5 activity in neural crest and melanoma, and contains dimeric SoxE binding sites essential for neural crest activity. Our work identifies a novel melanoma transcriptional enhancer, expanding our knowledge of epigenetic regulation of neural crest identity in melanoma.

The Ets-1 transcription factor is required for Stat1-mediated T-bet expression and IgG2a class switching in mouse B cells

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4174-4181 ◽  
Author(s):  
Hai Vu Nguyen ◽  
Enguerran Mouly ◽  
Karine Chemin ◽  
Romain Luinaud ◽  
Raymonde Despres ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
Molecular Mechanisms ◽  
Wild Type ◽  
Transcriptional Enhancer ◽  
T Box ◽  
Class Switch ◽  
Ifn Γ

Abstract In response to antigens and cytokines, mouse B cells undergo class-switch recombination (CSR) and differentiate into Ig-secreting cells. T-bet, a T-box transcription factor that is up-regulated in lymphocytes by IFN-γ or IL-27, was shown to regulate CSR to IgG2a after T cell–independent B-cell stimulations. However, the molecular mechanisms controlling this process remain unclear. In the present study, we show that inactivation of the Ets-1 transcription factor results in a severe decrease in IgG2a secretion in vivo and in vitro. No T-bet expression was observed in Ets-1–deficient (Ets-1−/−) B cells stimulated with IFN-γ and lipopolysaccharide, and forced expression of T-bet in these cells rescued IgG2a secretion. Furthermore, we identified a transcriptional enhancer in the T-bet locus with an activity in B cells that relies on ETS-binding sites. After IFN-γ stimulation of Ets-1−/− B cells, activated Stat1, which forms a complex with Ets-1 in wild-type cells, no longer binds to the T-bet enhancer or promotes histone modifications at this site. These results demonstrate that Ets-1 is critical for IgG2a CSR and acts as an essential cofactor for Stat1 in the regulation of T-bet expression in B cells.

scholarly journals Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life?

2007 ◽  
Vol 97 (6) ◽  
pp. 1036-1046 ◽  
Author(s):  
Graham C. Burdge ◽  
Mark A. Hanson ◽  
Jo L. Slater-Jefferies ◽  
Karen A. Lillycrop
Keyword(s):  
Epigenetic Regulation ◽  
Fetal Programming ◽  
Early Life ◽  
Disease Risk ◽  
Human Subjects ◽  
Covalent Modification ◽  
Regulation Of Transcription ◽  
Early Life Environment ◽  
And Function

There is considerable evidence for the induction of different phenotypes by variations in the early life environment, including nutrition, which in man is associated with a graded risk of metabolic disease; fetal programming. It is likely that the induction of persistent changes to tissue structure and function by differences in the early life environment involves life-long alterations to the regulation of gene transcription. This view is supported by both studies of human subjects and animal models. The mechanism which underlies such changes to gene expression is now beginning to be understood. In the present review we discuss the role of changes in the epigenetic regulation of transcription, specifically DNA methylation and covalent modification of histones, in the induction of an altered phenotype by nutritional constraint in early life. The demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life.

scholarly journals Epigenetic regulation of 5α reductase-1 underlies adaptive plasticity of reproductive function and pubertal timing

BMC Biology ◽  
2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Ben Bar-Sadeh ◽  
Or E. Amichai ◽  
Lilach Pnueli ◽  
Khurshida Begum ◽  
Gregory Leeman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ovarian Reserve ◽  
Early Life ◽  
Reproductive Function ◽  
Adaptive Plasticity ◽  
Mrna Levels ◽  
Altered Expression ◽  
Pubertal Onset ◽  
The Uk ◽  
Reproductive Phenotype

Abstract Background Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here, we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently, we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. Results Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5α reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women’s buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5α reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. Conclusions SRD5A1/5α reductase-1 responds epigenetically to the environment and its downregulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs.

Socio-Ecological Challenges as Modulators of Women's Reproductive Trajectories

2020 ◽  
Vol 49 (1) ◽  
pp. 317-336 ◽  
Author(s):  
Pablo A. Nepomnaschy ◽  
Amanda Rowlands ◽  
Ana Paula Prescivalli Costa ◽  
Katrina G. Salvante
Keyword(s):  
Reproductive Strategies ◽  
Evolutionary History ◽  
Life History Theory ◽  
Reproductive Function ◽  
Age At First Birth ◽  
Women's Bodies ◽  
Ecological Conditions ◽  
Challenges And Opportunities ◽  
The Moment ◽  
Pituitary Adrenal Axis

Amenorrhea, anovulatory cycles, miscarriages, and other reproductive outcomes are often seen as pathological. Life history theory, in contrast, treats those outcomes as adaptations that helped women optimize the timing of reproductive ventures across our evolutionary history. Women's bodies adjust their reproductive strategies in response to socio-ecological conditions, a process mediated by the hypothalamic-pituitary-adrenal axis (HPAA). Here, we review the links between socio-ecological conditions, HPAA activity, and the pace of women's reproductive transitions such as puberty, age at first birth, interbirth interval, and perimenopause. We also discuss the HPAA's role as a modulator of reproductive function: It not only suppresses it but may also prime women's bodies for future reproductive ventures. We conclude by reviewing challenges and opportunities within our subfield, including the need for transdisciplinary teams to develop longitudinal studies to improve our understanding of women's reproductive trajectories and outcomes from the moment they are conceived.

scholarly journals SUV39H1-mediated DNMT3A is participated in the epigenetic regulation of Tim-3 and galectin-9 in cervical cancer

2020 ◽  
Author(s):  
Li Zhang ◽  
Sijuan Tian ◽  
Minyi Zhao ◽  
Ting Yang ◽  
Shimin Quan ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Lines ◽  
Epigenetic Regulation ◽  
Promoter Region ◽  
Molecular Mechanisms ◽  
Expression System ◽  
Methylation Status ◽  
Regulation Mechanism

Abstract Background: Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are among the most highly conserved epigenetic marks that correlate well with gene silencing. The tumor microenvironment significantly influences therapeutic responses and clinical outcomes. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown.Methods: The methylation status of HAVCR2 and LGALS9 was detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanisms of SUV39H1-DNMT3A-Tim-3/galectin-9 regulation was elucidated using cervical cancer cell lines containing siRNA or/and over-expression system. Confirmation of the regulation of DNMT3A by SUV39H1 used ChIP-qPCR.Results: Here, we show that SUV39H1 up-regulates H3K9me3 expression in DNMT3A promoter region, which in turn induced expression of DNMT3A. In addition, our mechanistic studies indicate that DNMT3A mediates the epigenetic modulation of the HAVCR2 and LGALS9 genes by directly binding to their promoter regions in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1 up-regulates the level of H3K9me3 in the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 expression at the cellular level，indicating that SUV39H1-H3K9me3-DNMT3A is a crucial regulatory axis in cervical cancer.Conclusion: These results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.

scholarly journals SUV39H1-mediated DNMT3A is participated in the epigenetic regulation of Tim-3 and galectin-9 in cervical cancer

2020 ◽  
Author(s):  
Li Zhang ◽  
Sijuan Tian ◽  
Minyi Zhao ◽  
Ting Yang ◽  
Shimin Quan ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Lines ◽  
Epigenetic Regulation ◽  
Promoter Region ◽  
Molecular Mechanisms ◽  
Expression System ◽  
Methylation Status ◽  
Regulation Mechanism

Abstract Background: Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are among the most highly conserved epigenetic marks that correlate well with gene silencing. The tumor microenvironment significantly influences therapeutic responses and clinical outcomes. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown. Methods: The methylation status of HAVCR2 and LGALS9 was detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanisms of SUV39H1-DNMT3A-Tim-3/galectin-9 regulation was elucidated using cervical cancer cell lines containing siRNA or/and over-expression system. Confirmation of the regulation of DNMT3A by SUV39H1 used ChIP-qPCR. Results: Here, we show that SUV39H1 up-regulates H3K9me3 expression in DNMT3A promoter region, which in turn induced expression of DNMT3A. In addition, our mechanistic studies indicate that DNMT3A mediates the epigenetic modulation of the HAVCR2 and LGALS9 genes by directly binding to their promoter regions in vitro . Moreover, in an in vivo assay, the expression profile of SUV39H1 up-regulates the level of H3K9me3 in the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 expression at the cellular level，indicating that SUV39H1-H3K9me3-DNMT3A is a crucial regulatory axis in cervical cancer. Conclusion: These results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Sign in / Sign up

Export Citation Format

Share Document