scholarly journals Epigenetic Regulation of Mouse Sex Determination by the Histone Demethylase Jmjd1a

Science ◽  
2013 ◽  
Vol 341 (6150) ◽  
pp. 1106-1109 ◽  
Author(s):  
Shunsuke Kuroki ◽  
Shogo Matoba ◽  
Mika Akiyoshi ◽  
Yasuko Matsumura ◽  
Hitoshi Miyachi ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Sex Determination ◽  
Epigenetic Regulation ◽  
Sex Reversal ◽  
Histone Demethylase ◽  
Developmental Gene ◽  
Histone Demethylation ◽  
Developmental Gene Expression ◽  
Male To Female

Developmental gene expression is defined through cross-talk between the function of transcription factors and epigenetic status, including histone modification. Although several transcription factors play crucial roles in mammalian sex determination, how epigenetic regulation contributes to this process remains unknown. We observed male-to-female sex reversal in mice lacking the H3K9 demethylase Jmjd1a and found that Jmjd1a regulates expression of the mammalian Y chromosome sex-determining gene Sry. Jmjd1a directly and positively controls Sry expression by regulating H3K9me2 marks. These studies reveal a pivotal role of histone demethylation in mammalian sex determination.

scholarly journals Epigenetic regulation by the menin pathway

2017 ◽  
Vol 24 (10) ◽  
pp. T147-T159 ◽  
Author(s):  
Zijie Feng ◽  
Jian Ma ◽  
Xianxin Hua
Keyword(s):  
Transcription Factors ◽  
Cell Signaling ◽  
Signaling Pathways ◽  
Gene Transcription ◽  
Epigenetic Regulation ◽  
Posttranslational Modifications ◽  
Genetic Model ◽  
Mirna Biogenesis ◽  
Endocrine Organs

There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulation of several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of menin in epigenetic regulation of gene transcription and cell signaling, as well as posttranslational regulation of menin itself. In particular, we will review the progress in studying structural and functional interactions of menin with various histone modifiers and transcription factors such as MLL, PRMT5, SUV39H1 and other transcription factors including c-Myb and JunD. Moreover, the role of menin in regulating cell signaling pathways such as TGF-beta, Wnt and Hedgehog, as well as miRNA biogenesis and processing will be described. Further, the regulation of the MEN1 gene transcription, posttranslational modifications and stability of menin protein will be reviewed. These various modes of regulation by menin as well as regulation of menin by various biological factors broaden the view regarding how menin controls various biological processes in neuroendocrine organ homeostasis.

Role of mammalian Y chromosome in sex determination

1988 ◽  
Vol 322 (1208) ◽  
pp. 63-72 ◽  
Keyword(s):  
Cell Differentiation ◽  
Sex Determination ◽  
Y Chromosome ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Sex Reversal ◽  
Testicular Development ◽  
Chimeric Mouse ◽  
Embryonic Gonad

It has long been assumed that the mammalian Y chromosome either encodes, or controls the production of, a diffusible testis-determining molecule, exposure of the embryonic gonad to this molecule being all that is required to divert it along the testicular pathway. My recent finding that Sertoli cells in XX ↔ XY chimeric mouse testes are exclusively XY has led me to propose a new model in which the Y acts cell-autonomously to bring about Sertoli-cell differentiation. I have suggested that all other aspects of foetal testicular development are triggered by the Sertoli cells without further Y-chromosome involvement. This model thus equates mammalian sex determination with Sertoli-cell determination. Examples of natural and experimentally induced sex reversal are discussed in the context of this model.

Abstract 398: Histone Demethylase Kdm6a Contributes To X Chromosome Dependent Ischemia/reperfusion Injury Via Epigenetic Regulation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jingyuan Li ◽  
Yuichiro Itoh ◽  
Xuqi Chen ◽  
Arthur Arnold ◽  
Mansoureh Eghbali
Keyword(s):  
Sex Differences ◽  
Carbonic Anhydrase ◽  
X Chromosome ◽  
Epigenetic Regulation ◽  
Ischemia Reperfusion ◽  
Histone Demethylase ◽  
P Value ◽  
Rna Seq ◽  
Female Mice

Introduction: Sex differences in susceptibility to ischemia/reperfusion (I/R) injury have been mostly attributed to sex hormones. Recently we examined the role of sex chromosomes in sex differences in myocardial I/R injury. We discovered that gonadectomized mice with two X chromosomes (XX or XXY) have ~50% larger infarct size after I/R injury, compared to mice with one X chromosome (XY or XO). Only few X genes escape X inactivation and are expressed higher in XX than XY individuals. Here we examined the role of “X escapee” histone demethylase Kdm6a which is important in cardiac development. Methods: Female mice with a heterozygous global knockout of Kdm6a (Kdm6a+/-) and with 2 copies of Kdm6a (Kdm6a+/+, regular WT) were used. Isolated mouse hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion. RNA-Seq analysis was performed by comparing gene expression in hearts of Kdm6a+/+ vs. Kdm6a+/- females at baseline before ischemia. We calculated an unbiased composite score of relevance in which the level of significance of the Kdm6a effect on expression (p value) was integrated with the size of the KDM6A effect on expression (fold change), and with the amount of H3K27me3 mark found on the genes in the heart based on online ChIP-Seq data. Two way ANOVA was used for statistical analysis. P<0.05 was considered statistically significant. Values are expressed as mean± SE. Results: Kdm6a+/+ female mice had significantly lower heart functional recovery compared to their littermate Kdm6a+/- (LVDP: 46.7±9.8% vs. 79.8±3.5%; RPP: 44.1±10.5% vs. 76.2±8.5%, n=6-8 mice/group, p<0.01). The integration of our RNA-Seq data using the hearts of female mice with 2 vs. 1 copy of Kdm6a (n=4 samples per group) with online datasets measuring the H3K27me3 mark, sex differences in expression in humans and mice, and involvement in ischemic heart failure, revealed carbonic anhydrase-3 (Car3) as the most interesting candidate (upregulated ~7 fold in the hearts of Kdm6a+/+ vs. Kdm6a+/- female mice) at baseline. Car3 encodes one isoform of carbonic anhydrase, involved in pH regulation, which is a critical part of I/R injury. Conclusion: Histone demethylase KDM6A contributes to X chromosome dependent I/R injury via epigenetic regulation

scholarly journals Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009465
Author(s):  
Sarah L. Whiteley ◽  
Clare E. Holleley ◽  
Susan Wagner ◽  
James Blackburn ◽  
Ira W. Deveson ◽  
...  
Keyword(s):  
Sex Determination ◽  
Model Organism ◽  
Sex Reversal ◽  
Female Development ◽  
Cellular Mechanisms ◽  
Regulatory Pathways ◽  
Female Sex ◽  
Thermally Driven ◽  
Pogona Vitticeps ◽  
Male To Female

How temperature determines sex remains unknown. A recent hypothesis proposes that conserved cellular mechanisms (calcium and redox; ‘CaRe’ status) sense temperature and identify genes and regulatory pathways likely to be involved in driving sexual development. We take advantage of the unique sex determining system of the model organism, Pogona vitticeps, to assess predictions of this hypothesis. P. vitticeps has ZZ male: ZW female sex chromosomes whose influence can be overridden in genetic males by high temperatures, causing male-to-female sex reversal. We compare a developmental transcriptome series of ZWf females and temperature sex reversed ZZf females. We demonstrate that early developmental cascades differ dramatically between genetically driven and thermally driven females, later converging to produce a common outcome (ovaries). We show that genes proposed as regulators of thermosensitive sex determination play a role in temperature sex reversal. Our study greatly advances the search for the mechanisms by which temperature determines sex.

scholarly journals TET2 catalyzes active DNA demethylation of the Sry promoter and enhances its expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Naoki Okashita ◽  
Shunsuke Kuroki ◽  
Ryo Maeda ◽  
Makoto Tachibana
Keyword(s):  
Sex Determination ◽  
Gonadal Development ◽  
Sex Reversal ◽  
Dna Demethylation ◽  
Active Dna Demethylation ◽  
Specific Manner ◽  
Male Sex ◽  
Male To Female ◽  
Deficient Mice

Abstract SRY is the master regulator of male sex determination in eutherian mammals. In mice, Sry expression is transcriptionally and epigenetically controlled in a developmental stage-specific manner. The Sry promoter undergoes demethylation in embryonic gonadal somatic cells at the sex-determining period. However, its molecular mechanism and in vivo significance remain unclear. Here, we report that the Sry promoter is actively demethylated during gonadal development, and TET2 plays a fundamental role in Sry demethylation. Tet2-deficient mice showed absence of 5-hydroxymethylcytosine in the Sry promoter. Furthermore, Tet2 deficiency diminished Sry expression, indicating that TET2-mediated DNA demethylation regulates Sry expression positively. We previously showed that the deficiency of the H3K9 demethylase Jmjd1a compromises Sry expression and induces male-to-female sex reversal. Tet2 deficiency enhanced the sex reversal phenotype of Jmjd1a-deficient mice. Thus, TET2-mediated active DNA demethylation and JMJD1A-mediated H3K9 demethylation contribute synergistically to sex determination.

scholarly journals T-bet's Ability To Regulate Individual Target Genes Requires the Conserved T-Box Domain To Recruit Histone Methyltransferase Activity and a Separate Family Member-Specific Transactivation Domain

2007 ◽  
Vol 27 (24) ◽  
pp. 8510-8521 ◽  
Author(s):  
Megan D. Lewis ◽  
Sara A. Miller ◽  
Michael M. Miazgowicz ◽  
Kristin M. Beima ◽  
Amy S. Weinmann
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Function Analysis ◽  
Histone Methyltransferase ◽  
Transactivation Domain ◽  
Developmental Gene ◽  
Methyltransferase Activity ◽  
T Box ◽  
Developmental Gene Expression ◽  
Expression Pathways

ABSTRACT Appropriate cellular differentiation and specification rely upon the ability of key developmental transcription factors to precisely establish gene expression patterns. These transcription factors often regulate epigenetic events. However, it has been unclear whether this is the only role that they play in functionally regulating developmental gene expression pathways or whether they also participate in downstream transactivation events at the same promoter. The T-box transcription factor family is important in cellular specification events in many developmental systems, and determining the molecular mechanisms by which this family regulates gene expression networks warrants attention. Here, we examine the mechanism by which T-bet, a critical T-box protein in the immune system, influences transcription. T-bet is both necessary and sufficient to induce permissive histone H3-K4 dimethyl modifications at the CXCR3 and IFN-γ promoters. A T-bet structure-function analysis revealed that the conserved T-box domain, with a small C-terminal portion, is required for recruiting histone methyltransferase activity to promoters. Interestingly, this function is conserved in the T-box family and is necessary, but not sufficient, to induce transcription, with an independent transactivation activity also required. The requirement for two separable functional activities may ultimately contribute to the stringent role for T-box proteins in establishing specific developmental gene expression pathways.

scholarly journals Blockage of androgen and administration of estrogen induce transdifferentiation of testis into ovary

2017 ◽  
Vol 233 (1) ◽  
pp. 65-80 ◽  
Author(s):  
Hongjuan Shi ◽  
Tian Gao ◽  
Zhilong Liu ◽  
Lina Sun ◽  
Xiaolong Jiang ◽  
...  
Keyword(s):  
Sex Reversal ◽  
Glycyrrhetinic Acid ◽  
Simultaneous Administration ◽  
Steroidogenic Enzymes ◽  
Simultaneous Treatment ◽  
17Β Estradiol ◽  
Male Sex ◽  
Male To Female

Induction of sex reversal of XY fish has been restricted to the sex undifferentiated period. In the present study, differentiated XY tilapia were treated with trilostane (TR), metopirone (MN) and glycyrrhetinic acid (GA) (inhibitor of 3β-HSD, Cyp11b2 and 11β-HSD, respectively) alone or in combination with 17β-estradiol (E2) from 30 to 90 dah (days after hatching). At 180 dah, E2 alone resulted in 8.3%, and TR, MN and GA alone resulted in no secondary sex reversal (SSR), whereas TR + E2, MN + E2 and GA + E2 resulted in 88.3, 60.0 and 46.7% of SSR, respectively. This sex reversal could be rescued by simultaneous administration of 11-ketotestosterone (11-KT). Compared with the control XY fish, decreased serum 11-KT and increased E2 level were detected in SSR fish. Immunohistochemistry analyses revealed that Cyp19a1a, Cyp11b2 and Dmrt1 were expressed in the gonads of GA + E2, MN + E2 and TR + E2 SSR XY fish at 90 dah, but only Cyp19a1a was expressed at 180 dah. When the treatment was applied from 60 to 120 dah, TR + E2 resulted in 3.3% of SSR, MN + E2 and GA + E2 resulted in no SSR. These results demonstrated that once 11-KT was synthesized, it could antagonize E2-induced male-to-female SSR, which could be abolished by simultaneous treatment with the inhibitor of steroidogenic enzymes. The upper the enzyme was located in the steroidogenic pathway, the higher SSR rate was achieved when it was inhibited as some of the precursors, such as androstenedione, testosterone and 5α-dihydrotestosterone, could act as androgens. These results highlight the key role of androgen in male sex maintenance.

scholarly journals Dmrt1 mutation causes a male-to-female sex reversal after the sex determination by Dmy in the medaka

2011 ◽  
Vol 20 (1) ◽  
pp. 163-176 ◽  
Author(s):  
Haruo Masuyama ◽  
Masato Yamada ◽  
Yasuhiro Kamei ◽  
Tomoko Fujiwara-Ishikawa ◽  
Takeshi Todo ◽  
...  
Keyword(s):  
Sex Determination ◽  
Sex Reversal ◽  
Female Sex ◽  
Male To Female
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