Sex and the basal mRNA synthesis machinery.

Evolution and change generated an incredible diversity of organisms on this earth. Yet, some processes are so central to life that change is strongly selected against. Synthesis of the eukaryotic messenger RNA is one example. The assemblies that carry out transcription and processing (capping, polyadenylation, and splicing) are so conserved that most genes have recognizable orthologs in yeast and humans. Naturally, most would conclude transcription and processing are identical in both sexes. However, this is an assumption. Men and women vastly differ in their physiologies. The incidence of pathologies, symptom presentation, disease outcome, and therapeutic response in each sex vary enormously. Despite the harm ignorance causes women, biological research has been historically carried out without regard to sex. The male mouse was the default mammal. A cultured cell's sex was considered irrelevant. Attempts to fill this knowledge gap have revealed molecular dissimilarities. For example, the earliest embryonic male and female transcriptomes differ long before fetal sex hormones appear. We used public data to challenge the assumption of sameness by reviewing reports of sex-biased gene expression and gene targeting. We focused on 120 genes encoding nonregulatory proteins involved in mRNA synthesis. Remarkably, genes with recognizable orthologs in yeast and thus LEAST likely to differ, did differ between the sexes. The rapidly growing public databases can be used to compare the expression of any gene in male and female tissues. Appreciating the principles that drive sex differences will enrich our understanding of RNA biology in all humans-men and women. This article is categorized under: RNA in Disease and Development > RNA in Development RNA Evolution and Genomics > Computational Analyses of RNA.

Genetic background influences the impact of KLOTHO deficiency.

Genetic background is a key but sometimes overlooked factor that profoundly impacts disease susceptibility and presentation in both humans and disease models. Here we show that deficiency of KLOTHO protein, an important renal regulator of mineral homeostasis and a cofactor for FGF23, causes different phenotypes in 129S1/SvlmJ (129) and C57BL/6J (B6) mouse strains. The 129 strain is more severely affected, with decreased longevity, decreased body weight, and increased amounts of kidney calcification compared with B6 mice. Reciprocal F1 crosses of the strains also indicate a parentage effect on the Klotho phenotype with F1 KLOTHO-deficient progeny of B6 mothers and 129 fathers having more kidney calcification than progeny of 129 mothers and B6 fathers. Comparing and contrasting the genetic architecture leading to different phenotypes associated with specific inbred mouse strains may reveal previously unrecognized and important metabolic interactions affecting chronic kidney disease.

An autonomous BMP2 regulatory element in mesenchymal cells.

BMP2 is a morphogen that controls mesenchymal cell differentiation and behavior. For example, BMP2 concentration controls the differentiation of mesenchymal precursors into myocytes, adipocytes, chondrocytes, and osteoblasts. Sequences within the 3'untranslated region (UTR) of the Bmp2 mRNA mediate a post-transcriptional block of protein synthesis. Interaction of cell and developmental stage-specific trans-regulatory factors with the 3'UTR is a nimble and versatile mechanism for modulating this potent morphogen in different cell types. We show here, that an ultra-conserved sequence in the 3'UTR functions independently of promoter, coding region, and 3'UTR context in primary and immortalized tissue culture cells and in transgenic mice. Our findings indicate that the ultra-conserved sequence is an autonomously functioning post-transcriptional element that may be used to modulate the level of BMP2 and other proteins while retaining tissue specific regulatory elements.