Genome-Wide Analysis of Chromatin States Reveals Distinct Mechanisms of Sex-Dependent Gene Regulation in Male and Female Mouse Liver

Sugathan, Aarathi; Waxman, David J.

doi:10.1128/mcb.00280-13

Cited by 137 publications

(247 citation statements)

References 84 publications

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“…Action of these hormones extends at the epigenetic level to DNA methylation and chromatin conformation 16,17 . Analysis of gene expression in different non reproductive tissues indicates the existence of a gender specific influence on transcription 18,19 , which is paralleled at the level of chromatin organization, by specific differences between the sexes 20 . As discussed here below, sex hormone signaling pathways are likely to affect cancer susceptibility through multiple mechanisms, impacting on intrinsic self renewal mechanisms, tumor microenvironment, immune system and metabolism.…”

Section: Introduction (Epidemiology)mentioning

confidence: 99%

Sexual dimorphism in cancer

et al. 2016

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The incidence of many cancer types is significantly higher in the male than female populations, with associated differences in survival. Occupational and/or behavioral factors are well known underlying determinants. However, cellular/molecular differences between the two sexes are also likely to be important. We are focusing here on the complex interplay that sexual hormones and sex chromosomes can have in intrinsic control of cancer initiating cell populations, tumor microenvironment and systemic determinants of cancer development like the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.3 Introduction (Epidemiology)

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Section: Introduction (Epidemiology)mentioning

confidence: 99%

Sexual dimorphism in cancer

et al. 2016

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“…The downstream elements of this sex-bias mechanism are male versus female patterned secretion of GHRH from the hypothalamus into the hypophyseal portal circulation and then corresponding patterned secretion of GH by the pituitary into the general circulation. This finding was discovered by Edén in 1979 (55) and, since then, has been extensively confirmed in mice, rats and humans (27,(45)(46)(47)(48)(49)(50)(56)(57)(58)(59)(60)(61)(62). Circulating GH levels in the male (M) are usually called "pulsatile" (two to four peaks per day) with very low interpulse levels; in the female (F), there is a higher frequency of pulses (seven or more peaks per day) with significant interpulse levels; thus, this is called "more continuous" (Figures 1, 2).…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 88%

“…However, it was shown in 1973 by Colby et al (32), and extensively confirmed by numerous studies since then (27,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43), that the feminizing effect on sex-biased liver gene expression of an injection of E2 into a rat or mouse was indirect and had an absolute dependence on the pituitary ( Figure 1). As explained in detail by Waxman and colleagues over the last 2 decades, this neuroendocrine mechanism of sex bias, working through an axis consisting of the hypothalamic arcuate nucleus-growth hormone releasing hormone (GHRH)-growth hormone (GH)-signal transducer and activator of transcription 5 (STAT5) accounts for sex-biased expression of >1,000 genes in the liver and also of body growth and body weight (27,(41)(42)(43)(44)(45)(46)(47)(48) (Figures 2, 3). Parenthetically, STAT5 is the major transcription factor activated by the binding of GH to its receptor on all cell types (27,(41)(42)(43)(44)(45)(46)(47)(48).…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

“…As explained in detail by Waxman and colleagues over the last 2 decades, this neuroendocrine mechanism of sex bias, working through an axis consisting of the hypothalamic arcuate nucleus-growth hormone releasing hormone (GHRH)-growth hormone (GH)-signal transducer and activator of transcription 5 (STAT5) accounts for sex-biased expression of >1,000 genes in the liver and also of body growth and body weight (27,(41)(42)(43)(44)(45)(46)(47)(48) (Figures 2, 3). Parenthetically, STAT5 is the major transcription factor activated by the binding of GH to its receptor on all cell types (27,(41)(42)(43)(44)(45)(46)(47)(48). This activation involves Tyr phosphorylation of receptor-associated Janus kinases, with the latter then mediating Tyr phosphorylation of STAT5.…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

“…Thus, much of the biological activity of GH on different cell types is mediated by this activation of STAT5. From among the family of STAT transcription factors, STAT5a and STAT5b are the only transcription factors that mediate sex bias (27,(41)(42)(43)(44)(45)(46)(47)(48).…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

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Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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Pregnane X Receptor as the “Sensor and Effector” in Regulating Epigenome

Chen

Yan

2014

Journal Cellular Physiology

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The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor which plays an essential role in organism's metabolic detoxification system by sensing the presence of xenobiotics and triggering detoxification responses. In addition to its role in xenobiotic metabolism, PXR has pleiotropic functions in regulating immune/inflammatory responses, cell proliferation, bile acid/cholesterol metabolism, glucose and lipid metabolism, steroid/endocrine homeostasis, and bone metabolism. Recent research suggests that the PXR is required for maintaining healthy commensalism between microbiota and gut. Interestingly, the metabolites such as indole derivatives from commensal microbes serve as the ligands for the PXR in intestinal epithelium forming an intricate mutualistic interaction between host and microbiota. PXR-regulated gene responses are controlled at epigenetic level by chromatin modifications, DNA methylation and noncoding RNA. Developmental alterations of the epigenome by exposure to the xenobiotics or diseases may produce persistent changes in PXR-regulated physiological responses. These new areas of research promise to vastly increase our understanding of PXR-regulated responses. In this review we highlight recent results on the epigenetic mechanisms for the PXR-regulated gene expression and discuss the physiological significance of these findings.

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Genome-Wide Analysis of Chromatin States Reveals Distinct Mechanisms of Sex-Dependent Gene Regulation in Male and Female Mouse Liver

Cited by 137 publications

References 84 publications

Sexual dimorphism in cancer

Sexual dimorphism in cancer

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Pregnane X Receptor as the “Sensor and Effector” in Regulating Epigenome

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