Whole-genome sequence assemblies are now available for seven different animals, including nematode worms, mice and humans. Comparative genome analyses reveal a surprising constancy in genetic content: vertebrate genomes have only about twice the number of genes that invertebrate genomes have, and the increase is primarily due to the duplication of existing genes rather than the invention of new ones. How, then, has evolutionary diversity arisen? Emerging evidence suggests that organismal complexity arises from progressively more elaborate regulation of gene expression.

/pdf/transcription-regulation-and-animal-diversity-2qymt97v7s.pdf

Transcription regulation and animal diversity

Analysis of Development Edited by Prof Benjamin H Willier, Prof Paul A Weiss and Prof Viktor Hamburger Pp xii + 735 (Philadelphia and London: W B Saunders Company, 1955) 105s

Mechanisms of Development

In eukaryotes, the core promoter serves as a platform for the assembly of transcription preinitiation complex (PIC) that includes TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, and RNA polymerase II (pol II), which function collectively to specify the transcription start site. PIC formation usually begins with TFIID binding to the TATA box, initiator, and/or downstream promoter element (DPE) found in most core promoters, followed by the entry of other general transcription factors (GTFs) and pol II through either a sequential assembly or a preassembled pol II holoenzyme pathway. Formation of this promoter-bound complex is sufficient for a basal level of transcription. However, for activator-dependent (or regulated) transcription, general cofactors are often required to transmit regulatory signals between gene-specific activators and the general transcription machinery. Three classes of general cofactors, including TBP-associated factors (TAFs), Mediator, and upstream stimulatory activity (USA)-derived positive cofactors (PC1/PARP-1, PC2, PC3/DNA topoisomerase I, and PC4) and negative cofactor 1 (NC1/HMGB1), normally function independently or in combination to fine-tune the promoter activity in a gene-specific or cell-type-specific manner. In addition, other cofactors, such as TAF1, BTAF1, and negative cofactor 2 (NC2), can also modulate TBP or TFIID binding to the core promoter. In general, these cofactors are capable of repressing basal transcription when activators are absent and stimulating transcription in the presence of activators. Here we review the roles of these cofactors and GTFs, as well as TBP-related factors (TRFs), TAF-containing complexes (TFTC, SAGA, SLIK/SALSA, STAGA, and PRC1) and TAF variants, in pol II-mediated transcription, with emphasis on the events occurring after the chromatin has been remodeled but prior to the formation of the first phosphodiester bond.

The general transcription machinery and general cofactors.

miwi, a Murine Homolog of piwi, Encodes a Cytoplasmic Protein Essential for Spermatogenesis

The world's population is increasing at an alarming rate and is projected to reach nine billion by 2050. Despite this, 15% of couples world-wide remain childless because of infertility. Few genetic causes of infertility have been identified in humans; nevertheless, genetic aetiologies are thought to underlie many cases of idiopathic infertility. Mouse models with reproductive defects as a major phenotype are being rapidly created and discovered and now total over 200. These models are helping to define mechanisms of reproductive function, as well as identify potential new contraceptive targets and genes involved in the pathophysiology of reproductive disorders. With this new information, men and women will continue to be confronted with difficult decisions on whether or not to use state-of-the-art technology and hormonal treatments to propagate their germline, despite the risks of transmitting mutant genes to their offspring.

/pdf/genetic-dissection-of-mammalian-fertility-pathways-qyp7am5f59.pdf

Genetic dissection of mammalian fertility pathways.

The discovery of TATA-binding protein-related factors (TRFs) has suggested alternative mechanisms for gene-specific transcriptional regulation and raised interest in their biological functions. In contrast to recent observations of an embryonic lethal phenotype for TRF2 inactivation in Caenorhabditis elegans and Xenopus laevis, we found that Trf2-deficient mice are viable. However, Trf2-/- mice are sterile because of a severe defect in spermiogenesis. Postmeiotic round spermatids advance at most to step 7 of differentiation but fail to progress to the elongated form, and gene-specific transcription deficiencies were identified. We speculate that mammals may have evolved more specialized TRF2 functions in the testis that involve transcriptional regulation of genes essential for spermiogenesis.

http://science.sciencemag.org/content/sci/292/5519/1153.full.pdf

Spermiogenesis Deficiency in Mice Lacking the Trf2 Gene

Cell- and stage-specific high-level expression of TBP-related factor 2 (TRF2) during mouse spermatogenesis.

Contents continued


 
 
 Women with atrial fibrillation (AF) have been reported to receive less antiarrhythmic therapies (AAT) than men. We assessed sex differences in AAT use in Finland.
 
 
 
 The FinACAF registry linked data from several nationwide registries covering all levels of care in addition to drug purchases and included records on all patients diagnosed with incident AF in Finland during 2007–2018. The outcomes of interest (use of antiarrhythmic drugs (AAD), cardioversions (CV), catheter ablation procedures and any AAT including all aforementioned rhythm control modalities) were identified based on procedure-specific codes and drug purchases. Sex differences in AAT use were analyzed in the entire cohort and separately in three age groups: <65 years, 65–74 years and ≥75 years using Fine-Gray subdistribution hazard regression with death as a competing risk and adjustments made for comorbidities, age and levels of income and education.
 
 
 
 Altogether, 229565 patients (50.0% female; mean age 68.90±13.44 in men and 76.57±11.79 in women) with incident AF were identified. In the entire patient population, female sex was associated a higher incidence of AAD use and lower incidence of CVs and ablation procedures contributing to an overall slightly lower incidence of any AAT compared to men (Table 1). In the age group specific analyses, the lower incidence of CVs and higher incidence of AAD use in females were observed only in patients <65 years and <75 years, respectively, whereas the association of female sex with lower incidence of catheter ablation procedures was observed only in the age group ≥75 years.
 
 
 
 Our nationwide data showed no considerable sex difference in overall use of AAT in Finland. Despite a lower number of CVs in women, ablation procedures were performed almost equally and AADs were used more frequently in women compared to men.
 
 
 
 Type of funding sources: Foundation. Main funding source(s): Sydäntutkimussäätiö


https://academic.oup.com/eurheartj/article-pdf/43/Supplement_2/ehac544.561/46362538/ehac544.561.pdf

Tarja-Leena Penttila

Papers

Spermiogenesis Deficiency in Mice Lacking the Trf2 Gene

Cell- and stage-specific high-level expression of TBP-related factor 2 (TRF2) during mouse spermatogenesis.

Contents continued

Sex differences in the use of rhythm control strategies in patients with atrial fibrillation in FinACAF study