The evolving landscape of prostate cancer somatic mutations.

Background: The landscape of somatic mutations in prostate cancer (PCa) has quickly evolved over the past years.

Results: This evolution was in part due to the improved quality and lower cost of genomic sequencing platforms available to an ever-larger group of clinicians and researchers. The result of these efforts is a better understanding of early and late mutations that are enriched or nearly exclusive to treated PCa.

Mapping of mA and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.

Recent evidence has highlighted the role of -methyladenosine (mA) in the regulation of mRNA expression, stability, and translation, supporting a potential role for posttranscriptional regulation mediated by mA in cancer. Here, we explore prostate cancer as an exemplar and demonstrate that low levels of -adenosine-methyltransferase () is associated with advanced metastatic disease. To investigate this relationship, we generated the first prostate mA maps, and further examined how METTL3 regulates expression at the level of transcription, translation, and protein.

GRAM: A GeneRAlized Model to predict the molecular effect of a non-coding variant in a cell-type specific manner.

There has been much effort to prioritize genomic variants with respect to their impact on "function". However, function is often not precisely defined: sometimes it is the disease association of a variant; on other occasions, it reflects a molecular effect on transcription or epigenetics. Here, we coupled multiple genomic predictors to build GRAM, a GeneRAlized Model, to predict a well-defined experimental target: the expression-modulating effect of a non-coding variant on its associated gene, in a transferable, cell-specific manner.

Inherited determinants of early recurrent somatic mutations in prostate cancer.

Prostate cancer is a highly heritable molecularly and clinically heterogeneous disease. To discover germline events involved in prostate cancer predisposition, we develop a computational approach to nominate heritable facilitators of somatic genomic events in the context of the androgen receptor signaling. Here, we use a ranking score and benign prostate transcriptomes to identify a non-coding polymorphic regulatory element at 7p14.

Adaptive Significance of ERα Splice Variants in Killifish (Fundulus heteroclitus) Resident in an Estrogenic Environment.

The possibility that chronic, multigenerational exposure to environmental estrogens selects for adaptive hormone-response phenotypes is a critical unanswered question. Embryos/larvae of killifish from an estrogenic-polluted environment (New Bedford Harbor, MA [NBH]) compared with those from a reference site overexpress estrogen receptor alpha (ERα) mRNA but are hyporesponsive to estradiol. Analysis of ERα mRNAs in the two populations revealed differences in splicing of the gene encoding ERα (esr1).

Cloning of multiple ERα mRNA variants in killifish (Fundulus heteroclitus), and differential expression by tissue type, stage of reproduction, and estrogen exposure in fish from polluted and unpolluted environments.

To test the hypothesis that alternative splicing could be an adaptive mechanism for populations subject to multi-generational estrogenic exposures, we compared estrogen receptor alpha (ERα) splicing variants in two populations of killifish (Fundulus heteroclitus): one resident in an estrogenic polluted environment (New Bedford Harbor, NBH, MA, USA) and one from a relatively uncontaminated reference site (Scorton Creek, SC, MA, USA). In total we identified 19 ERα variants, each with deletions of one or more coding exons. Four of the variants with potential functional relevance were analyzed by qPCR to test for population differences in expression by tissue type, site, sex, seasonal reproductive status and estrogen treatment.

Multiple structurally distinct ERα mRNA variants in zebrafish are differentially expressed by tissue type, stage of development and estrogen exposure.

It is well established that estrogen-like environmental chemicals interact with the ligand-binding site of estrogen receptors (ERs) to disrupt transcriptional control of estrogen responsive targets. Here we investigate the possibility that estrogens also impact splicing decisions on estrogen responsive genes, such as that encoding ERα itself. Targeted PCR cloning was applied to identify six ERα mRNA variants in zebrafish.

Morpholino-mediated knockdown of ERα, ERβa, and ERβb mRNAs in zebrafish (Danio rerio) embryos reveals differential regulation of estrogen-inducible genes.

Genetically distinct estrogen receptor (ER) subtypes (ERα and ERβ) play a major role in mediating estrogen actions in vertebrates, but their unique and overlapping functions are not entirely clear. Although mammals have 1 gene of each subtype (ESR1 and ESR2), teleost fish have a single esr1 (ERα) and 2 esr2 (ERβa and ERβb) genes. To determine the in vivo role of different ER isoforms in regulating estrogen-inducible transcription targets, zebrafish (Danio rerio) embryos were microinjected with esr-specific morpholino (MO) oligonucleotides to disrupt splicing of the exon III/intron III junction in the DNA-binding domain.

Expression of GABAergic receptors in mouse taste receptor cells.

Background: Multiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD) for gamma-aminobutyric acid (GABA) is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABA(A) and GABA(C)) or metabotropic receptors (GABA(B)) while it is terminated by the re-uptake of GABA through transporters (GATs).