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author:("Chen, xqi")
1.  What a difference an X or Y makes: sex chromosomes, gene dose, and epigenetics in sexual differentiation 
Summary
A modern general theory of sex determination and sexual differentiation identifies the factors that cause sexual bias in gene networks, leading to sex differences in physiology and disease. The primary sex-biasing factors are those encoded on the sex chromosomes that are inherently different in the male and female zygote. These factors, and downstream factors such as gonadal hormones, act directly on tissues to produce sex differences, and to antagonize each other to reduce sex differences. Recent study of mouse models such as the Four Core Genotypes has begun to distinguish between direct effects of sex chromosome complement (XX vs. XY) and hormonal effects. Several lines of evidence implicate epigenetic processes in the control of sex differences, although a great deal of more information is needed about sex differences in the epigenome.
doi:10.1007/978-3-642-30726-3_4
PMCID: PMC4150872  PMID: 23027446
sex chromosome; Y chromosome; X chromosome; Four Core Genotypes; sexome; gene networks; hormones
2.  Cell-autonomous sex determination outside of the gonad 
The classic model of sex determination in mammals states that the sex of the individual is determined by the type of gonad that develops, which in turn determines the gonadal hormonal milieu that creates sex differences outside of the gonads. However, XX and XY cells are intrinsically different because of the cell-autonomous sex-biasing action of X and Y genes. Recent studies of mice, in which sex chromosome complement is independent of gonadal sex, reveal that sex chromosome complement has strong effects contributing to sex differences in phenotypes such as metabolism. Adult mice with two X chromosomes (relative to mice with one X chromosome) show dramatically greater increases in body weight and adiposity after gonadectomy, irrespective of their gonadal sex. When fed a high fat diet, XX mice develop striking hyperinsulinemia and fatty liver, relative to XY mice. The sex chromosome effects are modulated by the presence of gonadal hormones, indicating an interaction of the sex-biasing effects of gonadal hormones and sex chromosome genes. Other cell-autonomous sex chromosome effects are detected in mice in many phenotypes. Birds (relative to eutherian mammals) are expected to show more widespread cell-autonomous sex determination in non-gonadal tissues, because of ineffective sex chromosome dosage compensation mechanisms.
doi:10.1002/dvdy.23936
PMCID: PMC3672066  PMID: 23361913
sex chromosome; sex determination; X chromosome; Y chromosome; Z chromosome; W chromosome; sexual differentiation; androgens; estrogens
3.  The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance 
Background
Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement.
Methods
In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured.
Results
Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups.
Conclusions
We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions.
doi:10.1186/2042-6410-4-15
PMCID: PMC3751353  PMID: 23926958
Klinefelter; Sex chromosome trisomy; XXY; XYY; Mouse; X chromosome; Y chromosome; Body weight; Obesity
4.  Metabolic impact of sex chromosomes 
Adipocyte  2013;2(2):74-79.
Obesity and associated metabolic diseases are sexually dimorphic. To provide better diagnosis and treatment for both sexes, it is of interest to identify the factors that underlie male/female differences in obesity. Traditionally, sexual dimorphism has been attributed to effects of gonadal hormones, which influence numerous metabolic processes. However, the XX/XY sex chromosome complement is an additional factor that may play a role. Recent data using the four core genotypes mouse model have revealed that sex chromosome complement—independently from gonadal sex—plays a role in adiposity, feeding behavior, fatty liver and glucose homeostasis. Potential mechanisms for the effects of sex chromosome complement include differential gene dosage from X chromosome genes that escape inactivation, and distinct genomic imprints on X chromosomes inherited from maternal or paternal parents. Here we review recent data in mice and humans concerning the potential impact of sex chromosome complement on obesity and metabolic disease.
doi:10.4161/adip.23320
PMCID: PMC3661109  PMID: 23805402
metabolic disease; sex differences; obesity; food intake; fatty liver; circadian rhythm
5.  The Number of X Chromosomes Causes Sex Differences in Adiposity in Mice 
PLoS Genetics  2012;8(5):e1002709.
Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the “four core genotypes,” to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.
Author Summary
Differences exist between men and women in the development of obesity and related metabolic diseases such as type 2 diabetes and cardiovascular disease. Previous studies have focused on the sex-biasing role of hormones produced by male and female gonads, but these cannot account fully for the sex differences in metabolism. We discovered that removal of the gonads uncovers an important genetic determinant of sex differences in obesity—the presence of XX or XY sex chromosomes. We used a novel mouse model to tease apart the effects of male and female gonads from the effects of XX or XY chromosomes. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had increased body fat and ate more food during the sleep period. Mice with two X chromosomes also had accelerated weight gain, fatty liver, and hyperinsulinemia on a high fat diet. The higher expression levels of a subset of genes on the X chromosome that escape inactivation may influence adiposity and metabolic disease. The effect of X chromosome genes is present throughout life, but may become particularly significant with increases in longevity and extension of the period spent with reduced gonadal hormone levels.
doi:10.1371/journal.pgen.1002709
PMCID: PMC3349739  PMID: 22589744
6.  What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? 
The “four core genotypes” (FCG) model comprises mice in which sex chromosome complement (XX vs. XY) is unrelated to the animal's gonadal sex. The four genotypes are XX gonadal males or females, and XY gonadal males or females. The model allows one to measure (1) the differences in phenotypes caused by sex chromosome complement (XX vs. XY), (2) the differential effects of ovarian and testicular secretions, and (3) the interactive effects of (1) and (2). Thus, the FCG model provides new information regarding the origins of sex differences in phenotype that has not been available from studies that manipulate gonadal hormone levels in normal XY males and XX females. Studies of the FCG model have uncovered XX vs. XY differences in behaviors (aggression, parenting, habit formation, nociception, social interactions), gene expression (septal vasopressin), and susceptibility to disease (neural tube closure and autoimmune disease) not mediated by gonadal hormones. Some sex chromosome effects are mediated by sex differences in dose of X genes or their parental imprint. Future studies will identify the genes involved and their mechanisms of action.
doi:10.1016/j.yfrne.2008.11.001
PMCID: PMC3282561  PMID: 19028515
Sex chromosome; X chromosome; Y chromosome; Sex differences; Sexual differentiation; Nociception; Neural tube closure; Autoimmune disease; Addiction
7.  Sex Chromosome Complement Affects Nociception and Analgesia in Newborn Mice 
In animal studies of nociception, females are often more sensitive to painful stimuli, whereas males are often more sensitive to analgesia induced by μ agonists. Sex differences are found even at birth, and in adulthood are likely caused, at least in part, by differences in levels of gonadal hormones. Here we investigate nociception and analgesia in neonatal mice, and assess the contribution of the direct action of sex chromosome genes in hotplate and tail withdrawal tests. We used the four core genotypes mouse model, in which gonadal sex is independent of the complement of sex chromosomes (XX vs. XY). Mice were tested at baseline and then injected with μ-opioid agonist morphine (10mg/kg), or with the κ-opioid agonist U50,488H (U50, 12.5mg/Kg) with or without the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.1mg/kg). On the day of birth, XX mice showed faster baseline latencies than XY in tail withdrawal, irrespective of their gonadal type. Gonadal males showed greater effects of morphine than gonadal females in the hotplate test, irrespective of their sex chromosome complement. U50 and morphine were both effective analgesics in both tests, but MK-801 did not block the U50 effect. The results suggest that sex chromosome complement and gonadal secretions both contribute to sex differences in nociception and analgesia by the day of birth.
Perspective: Sex differences in pain may stem not only from the action of gonadal hormones on pain circuits, but from the sex-specific action of X and Y genes. Identification of sex chromosome genes causing sex differences could contribute to better pain therapy in females and males.
doi:10.1016/j.jpain.2008.06.001
PMCID: PMC2575001  PMID: 18635401
pain; sex difference; hotplate; tail withdrawal; sex chromosomes; neonate
8.  Sex Chromosome Complement Affects Nociception in Tests of Acute and Chronic Exposure to Morphine in Mice 
Hormones and behavior  2007;53(1):124-130.
We tested the role of sex chromosome complement and gonadal hormones in sex differences in several different paradigms measuring nociception and opioid analgesia using “four core genotypes” C57BL/6J mice. The genotypes include XX and XY gonadal males, and XX and XY gonadal females. Adult mice were gonadectomized and tested 3–4 weeks later, so that differences between sexes (mice with testes vs. ovaries) were attributable mainly to organizational effects of gonadal hormones, whereas differences between XX and XY mice were attributable to their complement of sex chromosomes. In experiment 1 (hotplate test of acute morphine analgesia), XX mice of both gonadal sexes had significantly shorter hotplate baseline latencies prior to morphine than XY mice. In experiment 2, (test of development of tolerance to morphine), mice were injected twice daily with 10mg/kg morphine or saline for 6 days. Saline or the competitive NMDA antagonist CPP [3-]2-carboxypiperazin-4yl)propyl-1-phospionic acid] (10mg/kg) was co-injected. On day 7, mice were tested for hotplate latencies before and after administration of a challenge dose of morphine (10mg/kg). XX mice showed shorter hotplate latencies than XY mice at baseline, and the XX-XY difference was greater following morphine. In experiment 3, mice were injected with morphine (10mg/Kg) or saline,15 minutes before intraplantar injection of formalin (5%/25µl). XX mice licked their hindpaw more than XY mice within 5 minutes of formalin injection. The results indicate that X- or Y-linked genes have direct effects, not mediated by gonadal secretions, on sex differences in two different types of acute nociception.
doi:10.1016/j.yhbeh.2007.09.003
PMCID: PMC2713052  PMID: 17956759
X chromosome; Y chromosome; pain; sex difference; hotplate; sex chromosomes
9.  An Sp1/Sp3 Binding Polymorphism Confers Methylation Protection 
PLoS Genetics  2008;4(8):e1000162.
Hundreds of genes show aberrant DNA hypermethylation in cancer, yet little is known about the causes of this hypermethylation. We identified RIL as a frequent methylation target in cancer. In search for factors that influence RIL hypermethylation, we found a 12-bp polymorphic sequence around its transcription start site that creates a long allele. Pyrosequencing of homozygous tumors revealed a 2.1-fold higher methylation for the short alleles (P<0.001). Bisulfite sequencing of cancers heterozygous for RIL showed that the short alleles are 3.1-fold more methylated than the long (P<0.001). The comparison of expression levels between unmethylated long and short EBV-transformed cell lines showed no difference in expression in vivo. Electrophorectic mobility shift assay showed that the inserted region of the long allele binds Sp1 and Sp3 transcription factors, a binding that is absent in the short allele. Transient transfection of RIL allele-specific transgenes showed no effects of the additional Sp1 site on transcription early on. However, stable transfection of methylation-seeded constructs showed gradually decreasing transcription levels from the short allele with eventual spreading of de novo methylation. In contrast, the long allele showed stable levels of expression over time as measured by luciferase and ∼2–3-fold lower levels of methylation by bisulfite sequencing (P<0.001), suggesting that the polymorphic Sp1 site protects against time-dependent silencing. Our finding demonstrates that, in some genes, hypermethylation in cancer is dictated by protein-DNA interactions at the promoters and provides a novel mechanism by which genetic polymorphisms can influence an epigenetic state.
Author Summary
The factors that guide DNA hypermethylation in cancer are poorly understood. We identified the candidate tumor-suppressor gene, RIL, as a frequent methylation target in cancer. Here, we report on a 12-bp polymorphic sequence around its transcription start site that creates a long allele. Methylation analysis showed that, in aging colon, colon cancer, and leukemias, the short allele had 2.1–3.1-fold higher methylation than the long allele (P<0.001). Short and long alleles had similar expression levels in EBV-transformed cell lines. Electrophorectic mobility shift assay showed that the inserted region of the long allele binds Sp1 and Sp3 transcription factors. Transfection of RIL allele-specific transgenes showed no effects of the additional Sp1 site on transcription early on, but methylation-seeded constructs showed gradually decreasing transcription from the short allele with eventual spreading of de novo methylation. By contrast, the long allele showed stable expression over time as measured by luciferase, and ∼2–3-fold lower levels of methylation by bisulfite sequencing (P<0.001), suggesting that the polymorphic Sp1 site protects against time-dependent silencing. Our finding demonstrates that in some genes, hypermethylation in cancer is dictated by protein-DNA interactions at the promoters and provides a novel mechanism by which genetic polymorphisms can influence an epigenetic state.
doi:10.1371/journal.pgen.1000162
PMCID: PMC2515197  PMID: 18725933

Results 1-9 (9)