Sex and the basal mRNA synthesis machinery

Abstract

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.

X-chromosome inactivation patterns depend on age and tissue but not conception method in humans

“…The CD44 molecule (Indian blood group), a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion, and migration, plays a role in maintaining the placental structural integrity (Lambertini et al 2012 ; Moore et al 2015 ), while PHLDA2—the pleckstrin homology-like domain family A member 2—regulates the placenta growth (Tunster et al 2010 ; Lambertini et al 2012 ; Moore et al 2015 ). Further, the loss of ZRSR2 (zinc finger CCCH-type, RNA-binding motif, and serine-/arginine-rich 2 protein), a component of the minor spliceosome (Garsetti et al 2022 ), inhibits cell growth and alters the in vitro differentiation potential of haematopoietic cells (Madan et al 2015 ). We hypothesize that certain levels of transcription of these genes may affect survival or growth rate resulting in the proliferative advantage of one pool of cells over the others in a mosaic tissue, ultimately leading to a substantial XCI skewing.…”

The HNRNPF/H RNA binding proteins and disease

“…(b) An overview of gene level expression of each HNRNPF/H family member assessed using bulk RNA sequencing of selected human tissues. Data extracted from GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2; please note the sampling biases in these datasets discussed in Garsetti et al (2022).…”

“…The organization and expression of selected (a) HNRNPF , (b) HNRNPH1 , (c) HNRNPH2 , (d) HNRNPH3 , and (e) GRSF1 transcript variants in selected tissues. Data extracted from GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2; please note the sampling biases in these datasets discussed in Garsetti et al (2022). The arrow indicates the direction of expression.…”