Estradiol synthesis within the human brain

Estradiol biosynthesis is catalyzed by the enzyme aromatase, the product of the CYP19A1 gene. Aromatase is expressed in the brain, where it is involved not only in the control of neuroendocrine events and reproduction, but also in the regulation of neural development, synaptic plasticity and cell survival. In this review we summarize the existing data related with the detection of aromatase in human brain, with particular emphasis in the so-called “non-primary reproductive” areas. Besides hypothalamus, amygdala and preoptic/septal areas, aromatase is expressed in certain regions of basal forebrain, cerebral cortex, hippocampus, thalamus, cerebellum and brainstem of the human brain. Aromatase in human brain is produced by neurons, but there is also an astrocyte subpopulation that constitutively expresses the enzyme. The use of different methodological approaches, including the in vivo analysis by positron emission tomography of human subjects, has permitted to draw a general map of human brain aromatase, but the detailed distribution map is still far to be completed. On the other hand, despite the fact that there is only one aromatase protein, there are multiple mRNA transcripts that differ in the 5'-untranslated region, where regulatory elements reside. To date, some of the aromatase transcripts characteristic of cerebral cortex, as well as of human cell lines of neural origin, have been identified. This characteristic may confer tissue or even region-specific regulation of the expression and therefore it is conceivable to develop selective aromatase modulators to regulate the expression of the enzyme in the human brai

CD28 Costimulation Regulates Genome-Wide Effects on Alternative Splicing

CD28 is the major costimulatory receptor required for activation of naïve T cells, yet CD28 costimulation affects the expression level of surprisingly few genes over those altered by TCR stimulation alone. Alternate splicing of genes adds diversity to the proteome and contributes to tissue-specific regulation of genes. Here we demonstrate that CD28 costimulation leads to major changes in alternative splicing during activation of naïve T cells, beyond the effects of TCR alone. CD28 costimulation affected many more genes through modulation of alternate splicing than by modulation of transcription. Different families of biological processes are over-represented among genes alternatively spliced in response to CD28 costimulation compared to those genes whose transcription is altered, suggesting that alternative splicing regulates distinct biological effects. Moreover, genes dependent upon hnRNPLL, a global regulator of splicing in activated T cells, were enriched in T cells activated through TCR plus CD28 as compared to TCR alone. We show that hnRNPLL expression is dependent on CD28 signaling, providing a mechanism by which CD28 can regulate splicing in T cells and insight into how hnRNPLL can influence signal-induced alternative splicing in T cells. The effects of CD28 on alternative splicing provide a newly appreciated means by which CD28 can regulate T cell responses

Disease-Aging Network Reveals Significant Roles of Aging Genes in Connecting Genetic Diseases

One of the challenging problems in biology and medicine is exploring the underlying mechanisms of genetic diseases. Recent studies suggest that the relationship between genetic diseases and the aging process is important in understanding the molecular mechanisms of complex diseases. Although some intricate associations have been investigated for a long time, the studies are still in their early stages. In this paper, we construct a human disease-aging network to study the relationship among aging genes and genetic disease genes. Specifically, we integrate human protein-protein interactions (PPIs), disease-gene associations, aging-gene associations, and physiological system–based genetic disease classification information in a single graph-theoretic framework and find that (1) human disease genes are much closer to aging genes than expected by chance; and (2) diseases can be categorized into two types according to their relationships with aging. Type I diseases have their genes significantly close to aging genes, while type II diseases do not. Furthermore, we examine the topological characters of the disease-aging network from a systems perspective. Theoretical results reveal that the genes of type I diseases are in a central position of a PPI network while type II are not; (3) more importantly, we define an asymmetric closeness based on the PPI network to describe relationships between diseases, and find that aging genes make a significant contribution to associations among diseases, especially among type I diseases. In conclusion, the network-based study provides not only evidence for the intricate relationship between the aging process and genetic diseases, but also biological implications for prying into the nature of human diseases

Whole Transcriptome Sequencing Reveals Gene Expression and Splicing Differences in Brain Regions Affected by Alzheimer's Disease

Recent studies strongly indicate that aberrations in the control of gene expression might contribute to the initiation and progression of Alzheimer's disease (AD). In particular, alternative splicing has been suggested to play a role in spontaneous cases of AD. Previous transcriptome profiling of AD models and patient samples using microarrays delivered conflicting results. This study provides, for the first time, transcriptomic analysis for distinct regions of the AD brain using RNA-Seq next-generation sequencing technology. Illumina RNA-Seq analysis was used to survey transcriptome profiles from total brain, frontal and temporal lobe of healthy and AD post-mortem tissue. We quantified gene expression levels, splicing isoforms and alternative transcript start sites. Gene Ontology term enrichment analysis revealed an overrepresentation of genes associated with a neuron's cytological structure and synapse function in AD brain samples. Analysis of the temporal lobe with the Cufflinks tool revealed that transcriptional isoforms of the apolipoprotein E gene, APOE-001, -002 and -005, are under the control of different promoters in normal and AD brain tissue. We also observed differing expression levels of APOE-001 and -002 splice variants in the AD temporal lobe. Our results indicate that alternative splicing and promoter usage of the APOE gene in AD brain tissue might reflect the progression of neurodegeneration

A Dominant Negative ERβ Splice Variant Determines the Effectiveness of Early or Late Estrogen Therapy after Ovariectomy in Rats

The molecular mechanisms for the discrepancy in outcome of initiating estrogen therapy (ET) around peri-menopause or several years after menopause in women are unknown. We hypothesize that the level of expression of a dominant negative estrogen receptor (ER) β variant, ERβ2, may be a key factor determining the effectiveness of ET in post-menopausal women. We tested this hypothesis in ovariectomized nine month-old (an age when irregular estrous cycles occur) female Sprague Dawley rats. Estradiol treatment was initiated either 6 days (Early ET, analogous to 4 months post-menopause in humans), or 180 days (Late ET, analogous to 11 years post-menopause in humans) after ovariectomy. Although ERβ2 expression increased in all OVX rats, neurogenic and neuroprotective responses to estradiol differed in Early and Late ET. Early ET reduced ERβ2 expression in both hippocampus and white blood cells, increased the hippocampal cell proliferation as assessed by Ki-67 expression, and improved mobility in the forced swim test. Late ET resulted in either no or modest effects on these parameters. There was a close correlation between the degree of ERβ2 expression and the preservation of neural effects by ET after OVX in rats, supporting the hypothesis that persistent elevated levels of ERβ2 are a molecular basis for the diminished effectiveness of ET in late post-menopausal women. The correlation between the expression of ERβ2 in circulating white blood cells and brain cells suggests that ERβ2 expression in peripheral blood cells may be an easily accessible marker to predict the effective window for ET in the brain

Alterations in the human brain in menopause

In a series of studies we showed that menopause in women causes alterations not only in the neuronal expression of estrogen receptors (ER) alpha and beta, but also in local estrogen production in several brain areas and in the rate of neuronal metabolism. Although such changes are clearly brain region-specific, there seems to be no evidence at present for a decrease in neuronal metabolic rate. On the contrary, an increase in the neuronal metabolic activity and in the level of ERalpha in postmenopausal women was noted. In the supraoptic nucleus (SON) that is a major source of plasma arginine-vasopressin (AVP) we found that neuronal metabolic activity as judged from the Golgi apparatus and cell size was markedly enhanced in women after menopause accompanied by an increase in ERalpha and a decrease in ERbeta. Similar changes were noted in the medial mamillary nucleus and in the hippocampus that are involved in the regulation of learning and memory. Recently we aimed at determining whether in addition to the canonical ERalpha and ERbeta, estrogen receptor splice variants lacking entire exons may also be involved in the menopause-associated changes in the human brain. We detected del. 2 (missing exon 2), del. 4 (lacking exon 4), del. 7 (exon 7 absent) and MB1 (deletion of 168 nucleotides in the exon 1) in the frozen hippocampal tissue of 6 women (46, 52, 59, 64, 77 and 83 years of age). No age-related changes were observed for the mentioned splice forms in women of this group.