scholarly journals The Nuclear Receptor Corepressor Has Organizational Effects within the Developing Amygdala on Juvenile Social Play and Anxiety-Like Behavior

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1212-1220 ◽  
Author(s):  
Heather M. Jessen ◽  
Mira H. Kolodkin ◽  
Meaghan E. Bychowski ◽  
Catherine J. Auger ◽  
Anthony P. Auger
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Social Play ◽  
Play Behavior ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Estradiol Treatment ◽  
Nuclear Receptor Corepressor ◽  
Males And Females

Nuclear receptor function on DNA is regulated by the balanced recruitment of coregulatory complexes. Recruited proteins that increase gene expression are called coactivators, and those that decrease gene expression are called corepressors. Little is known about the role of corepressors, such as nuclear receptor corepressor (NCoR), on the organization of behavior. We used real-time PCR to show that NCoR mRNA levels are sexually dimorphic, that females express higher levels of NCoR mRNA within the developing amygdala and hypothalamus, and that NCoR mRNA levels are reduced by estradiol treatment. To investigate the functional role of NCoR on juvenile social behavior, we infused small interfering RNA targeted against NCoR within the developing rat amygdala and assessed the enduring impact on juvenile social play behavior, sociability, and anxiety-like behavior. As expected, control males exhibited higher levels of juvenile social play than control females. Reducing NCoR expression during development further increased juvenile play in males only. Interestingly, decreased NCoR expression within the developing amygdala had lasting effects on increasing juvenile anxiety-like behavior in males and females. These data suggest that the corepressor NCoR functions to blunt sex differences in juvenile play behavior, a sexually dimorphic and hormone-dependent behavior, and appears critical for appropriate anxiety-like behavior in juvenile males and females.

scholarly journals Are sex-biased genes more dispensable?

2009 ◽  
Vol 5 (3) ◽  
pp. 409-412 ◽  
Author(s):  
Judith E. Mank ◽  
Hans Ellegren
Keyword(s):  
Gene Expression ◽  
Sexual Selection ◽  
Molecular Evolution ◽  
Gene Expression Pattern ◽  
Selective Constraint ◽  
Sexually Dimorphic ◽  
Males And Females ◽  
Natural And Sexual Selection ◽  
Rates Of Molecular Evolution

Many genes show different expression levels in males and females, and these form the basis of sexually dimorphic phenotypes. Sex-biased genes experience accelerated rates of protein evolution, which has been attributed to sexual selection. However, it is possible that the increased rates of molecular evolution, and more importantly the sex-biased gene expression pattern itself, are due to decreased selective constraint. This notion may explain many of the patterns associated with sex-biased gene expression, and changes how we should view the role of natural and sexual selection in relation to these genes.

DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Epigenomics ◽  
2021 ◽  
Author(s):  
Beatriz Garcia-Ruiz ◽  
Manuel Castro de Moura ◽  
Gerard Muntané ◽  
Lourdes Martorell ◽  
Elena Bosch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bipolar Disorder ◽  
Mrna Expression ◽  
Gene Expression Analysis ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide ◽  
Isoform Expression

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

scholarly journals Direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

2019 ◽  
Vol 116 (20) ◽  
pp. 9893-9902 ◽  
Author(s):  
Christopher M. Uyehara ◽  
Daniel J. McKay
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Transcriptional Responses ◽  
Enhancer Activity ◽  
Developmental Transitions ◽  
Experimental Systems ◽  
The Impact

The ecdysone pathway was among the first experimental systems employed to study the impact of steroid hormones on the genome. In Drosophila and other insects, ecdysone coordinates developmental transitions, including wholesale transformation of the larva into the adult during metamorphosis. Like other hormones, ecdysone controls gene expression through a nuclear receptor, which functions as a ligand-dependent transcription factor. Although it is clear that ecdysone elicits distinct transcriptional responses within its different target tissues, the role of its receptor, EcR, in regulating target gene expression is incompletely understood. In particular, EcR initiates a cascade of transcription factor expression in response to ecdysone, making it unclear which ecdysone-responsive genes are direct EcR targets. Here, we use the larval-to-prepupal transition of developing wings to examine the role of EcR in gene regulation. Genome-wide DNA binding profiles reveal that EcR exhibits widespread binding across the genome, including at many canonical ecdysone response genes. However, the majority of its binding sites reside at genes with wing-specific functions. We also find that EcR binding is temporally dynamic, with thousands of binding sites changing over time. RNA-seq reveals that EcR acts as both a temporal gate to block precocious entry to the next developmental stage as well as a temporal trigger to promote the subsequent program. Finally, transgenic reporter analysis indicates that EcR regulates not only temporal changes in target enhancer activity but also spatial patterns. Together, these studies define EcR as a multipurpose, direct regulator of gene expression, greatly expanding its role in coordinating developmental transitions.

scholarly journals MOZ and BMI1 play opposing roles during Hox gene activation in ES cells and in body segment identity specification in vivo

2015 ◽  
Vol 112 (17) ◽  
pp. 5437-5442 ◽  
Author(s):  
Bilal N. Sheikh ◽  
Natalie L. Downer ◽  
Belinda Phipson ◽  
Hannah K. Vanyai ◽  
Andrew J. Kueh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Es Cells ◽  
Gene Activation ◽  
Embryonic Stem ◽  
Mrna Levels ◽  
Body Segment ◽  
Initial Activation ◽  
Activation Phase

Hox genes underlie the specification of body segment identity in the anterior–posterior axis. They are activated during gastrulation and undergo a dynamic shift from a transcriptionally repressed to an active chromatin state in a sequence that reflects their chromosomal location. Nevertheless, the precise role of chromatin modifying complexes during the initial activation phase remains unclear. In the current study, we examined the role of chromatin regulators during Hox gene activation. Using embryonic stem cell lines lacking the transcriptional activator MOZ and the polycomb-family repressor BMI1, we showed that MOZ and BMI1, respectively, promoted and repressed Hox genes during the shift from the transcriptionally repressed to the active state. Strikingly however, MOZ but not BMI1 was required to regulate Hox mRNA levels after the initial activation phase. To determine the interaction of MOZ and BMI1 in vivo, we interrogated their role in regulating Hox genes and body segment identity using Moz;Bmi1 double deficient mice. We found that the homeotic transformations and shifts in Hox gene expression boundaries observed in single Moz and Bmi1 mutant mice were rescued to a wild type identity in Moz;Bmi1 double knockout animals. Together, our findings establish that MOZ and BMI1 play opposing roles during the onset of Hox gene expression in the ES cell model and during body segment identity specification in vivo. We propose that chromatin-modifying complexes have a previously unappreciated role during the initiation phase of Hox gene expression, which is critical for the correct specification of body segment identity.

scholarly journals Sex differences in gene expression and proliferation are dependent on the epigenetic modifier HP1γ

2019 ◽  
Author(s):  
Pui-Pik Law ◽  
Ping-Kei Chan ◽  
Kirsten McEwen ◽  
Huihan Zhi ◽  
Bing Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Sex Chromosome ◽  
Chromosome Complement ◽  
Autosomal Gene ◽  
Sexually Dimorphic ◽  
Heterochromatin Protein 1 ◽  
Epigenetic Modifier ◽  
Early Embryos ◽  
Males And Females

SummarySex differences in growth rate in very early embryos have been recognized in a variety of mammals and attributed to sex-chromosome complement effects as they occur before overt sexual differentiation. We previously found that sex-chromosome complement, rather than sex hormones regulates heterochromatin-mediated silencing of a transgene and autosomal gene expression in mice. Here, sex dimorphism in proliferation was investigated. We confirm that male embryonic fibroblasts proliferate faster than female fibroblasts and show that this proliferation advantage is completely dependent upon heterochromatin protein 1 gamma (HP1γ). To determine whether this sex-regulatory effect of HP1γ was a more general phenomenon, we performed RNA sequencing on MEFs derived from males and females, with or without HP1γ. Strikingly, HP1γ was found to be crucial for regulating nearly all sexually dimorphic autosomal gene expression because deletion of the HP1γ gene in males abolished sex differences in autosomal gene expression. The identification of a key epigenetic modifier as central in defining gene expression differences between males and females has important implications for understanding physiological sex differences and sex bias in disease.

scholarly journals Analysis of Hypothalamic TRH Neurons in Regulating Thyroid Hormone Levels

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A849-A849
Author(s):  
Ricardo H Costa e Sousa ◽  
Rodrigo Rorato ◽  
Anthony Neil Hollenberg ◽  
Kristen R Vella
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Designer Drugs ◽  
Mrna Levels ◽  
Hormone Levels ◽  
Males And Females ◽  
Thyroid Hormone Levels ◽  
Hpt Axis ◽  
Tsh Levels

Abstract Thyroid hormone (TH) is a major regulator of development and metabolism. An important mechanism controlling TH production is the negative feedback at the hypothalamic and pituitary level and it has been suggested that thyroid hormone receptor β (TRβ) is the main mediator of TH actions in the hypothalamic paraventricular nucleus (PVN). Nevertheless, the direct actions of TH and TRβ in the negative regulation of TRH have yet to be demonstrated in vivo. Here we used two approaches to investigate the TRH neuron. First, we used a chemogenetic tool to directly investigate the role of TRH neurons on the regulation of thyroid hormone levels. Mice expressing Cre-recombinase in TRH neurons received bilateral injections of the activating designer receptors exclusively activated by designer drugs (DREADD) directly into the PVN. Activation of TRH neurons produced a rapid and sustained increase in circulating TSH levels in both males and females. TSH levels increased approximately 10-fold from baseline within 15 minutes of injection of CNO, returning to baseline within 2.5 hours. TH levels were increased approximately 2-fold in males and females. Therefore, using a chemogenetic approach, we were able to directly evaluated the role of PVN TRH neurons on the control of thyroid activity, for the first time. Next, we generated mice deficient in TRβ specifically in neurons expressing melanocortin 4 receptor (MC4R), which overlaps with TRH expression in the PVN. Knockout mice (KO) developed normally and showed no change in TH and TSH levels. TRH mRNA levels in the PVN of KO mice were similar to control mice. To investigate if the deletion of TRβ in the PVN changes the sensitivity of the HPT axis to T3, mice were rendered hypothyroid and given increasing doses of T3 for 2 weeks. Results show no difference in TRH mRNA or serum TSH between controls and KO. Surprisingly, despite the presence of detectable genomic recombination on the TRβ gene in the PVN, there was no difference in TRβ mRNA expression between control and KO mice, suggesting that either MC4R-positive neurons do not express TRβ or they represent a very small population of TRβ-positive cells in the PVN. Present data show that TRH neuron activation rapidly stimulates TSH release and increases TH levels, demonstrating a major role of these neurons in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Nevertheless, deletion of TRβ from MC4R neurons had no major effect on either TRH or TH levels in in mice. Additionally, TRβ in MC4R-positive TRH neurons in the PVN is not necessary for TH-induced suppression of TRH mRNA. Although further studies are necessary, these data suggest that there are distinct populations of hypophysiotropic TRH neurons in the PVN, some of which are not regulated by thyroid hormone and TRβ.

Abstract P787: Sexually Dimorphic Gene Expression Molecular Correlates of Improvement in Human Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Hajar Amini ◽  
Bodie Knepp ◽  
Heather Hull ◽  
Paulina Carmona-Mora ◽  
Marisa Hakoupian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Factors ◽  
Protein Synthesis ◽  
Sex Differences ◽  
Ischemic Stroke ◽  
Major Protein ◽  
Sexually Dimorphic ◽  
Stroke Outcome ◽  
Males And Females ◽  
Dimorphic Gene Expression

Objective: Ischemic stroke (IS) is sexually dimorphic for risk factors, age, heritability, causes, treatment, and outcome. We identified transcriptional correlates with 90-day outcome that differed between male and female IS subjects. Methods: RNA from 72 samples from 2 peripheral blood draws (at ≤3 and 24h post IS onset) was analyzed on Affymetrix U133 Plus 2 microarrays. These represented samples from 36 CLEAR trial IS patients treated with tPA with or without eptifibatide after the first blood sample within 3 hours of stroke onset. Changes in gene expression levels (deltaGE) between 3h and 24h were calculated and the association with percent NIH Stroke Scale (NIHSS) improvement from 3h to 90 days (% Improvement) examined. We used mixed-effects linear regression, including Treatment, Age, Sex, Vascular Risk Factors, 3h NIHSS, % Improvement, and a Sex * % Improvement interaction. Sex differences in association of gene expression with % Improvement were determined by examining the Sex * % Improvement interaction term, p<0.005 was considered statistically significant. Results: 577 genes correlated differently with % Improvement in IS males and females. These included matrix metalloproteinases (MMPs), which play a major role in BBB dysfunction and outcomes post IS. MMP11 , MMP14 and MM17 correlated with % Improvement in opposite direction in males and females. Inflammatory genes like IL-27 , implicated in infarct volume and stroke outcome, and ABC transporters ( ABCC9 ) also had opposite correlation with % Improvement in males and females. Calmodulin 1 ( CAML1 ) was also sexually dimorphic, and a SNP in CALM1 has been implicated in IS risk and blood coagulation in female IS patients. EIF2 signaling, a major protein synthesis pathway was activated in males (adj. p = 1e-8), while suppressed in females (adj. p value = 1e-9). Protein synthesis and associated unfolded protein response cascade have previously been implicated in stroke outcome. Conclusions: The identified sexually dimorphic gene expression associated with 90-day improvement might relate to sex differences in blood immune and clotting pathways. The findings expand our understanding of the genomic underpinnings associated with stroke outcome and may serve as potential sex-specific treatment targets.

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