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While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWASs), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of functional genomic annotations in human cell types relevant to pregnancy and PTB. We generated transcriptome (RNA-seq), epigenome (ChIP-seq of H3K27ac, H3K4me1, and H3K4me3 histone modifications), open chromatin (ATAC-seq), and chromatin interaction (promoter capture Hi-C) annotations of cultured primary decidua-derived mesenchymal stromal/stem cells and in vitro differentiated decidual stromal cells and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. Using these resources, we uncovered additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

A new biomimetic model complex of the active site of acireductone dioxygenase (ARD) was synthesized and crystallographically characterized ([Ni(II)(N-(ethyl-N′Me 2)(Py)(2-t-ButPhOH))(OTf)]- 1). 1 displays carbon–carbon oxidative cleavage activity in the presence of O2 towards the substrate 2-hydroxyacetophenone. This reactivity was monitored via UV-Visible and NMR spectroscopy. We postulate that the reactivity of 1 with O2 leads to the formation of a putative Ni(III)-superoxo transient species resulting from the direct activation of O2via the nickel center during the oxidative reaction. This proposed intermediate and reaction mechanism were studied in detail using DFT calculations. 1 and its substrate bound derivatives display reactivity toward mild outer sphere oxidants, suggesting ease of access to high valent Ni coordination complexes, consistent with our calculations. If confirmed, the direct activation of O2 at a nickel center could have implications for the mechanism of action of ARD and other nickel-based dioxygenases and their respective non-traditional, enzymatic moonlighting functions, as well as contribute to a general understanding of direct oxidation of nickel(II) coordination complexes by O2. [ABSTRACT FROM AUTHOR]

There is a longstanding interest in whether the loss of complex characters is reversible (so‐called "Dollo's law"). Reevolution has been suggested for numerous traits but among the first was Kurtén, who proposed that the presence of the second lower molar (M2) of the Eurasian lynx (Lynx lynx) was a violation of Dollo's law because all other Felids lack M2. While an early and often cited example for the reevolution of a complex trait, Kurtén and Werdelin used an ad hoc parsimony argument to support their. Here I revisit the evidence that M2 reevolved lynx using explicit parsimony and maximum likelihood models of character evolution and find strong evidence that Kurtén and Werdelin were correct—M2 reevolved in E. lynx. Next, I explore the developmental mechanisms which may explain this violation of Dollo's law and suggest that the reevolution of lost complex traits may arise from the reevolution of cis‐regulatory elements and protein−protein interactions, which have a longer half‐life after silencing that protein coding genes. Finally, I present a developmental model to explain the reevolution M2 in E. lynx, which suggest that the developmental programs required for the establishment of serially homologous characters may never really be lost so long as a single instance of the character remains—thus the gain and loss and regain of serially homologous characters, such mammalian molars, may be developmentally and evolutionarily "simple." Research highlights: There is a growing interest in and renewed debate over whether the loss of complex characters is reversible. Kurtén suggested that the second lower molar (M2) recently reevolved in the Eurasian lynx. A simple model suggest that shared developmental genetic programs make the gain and loss and regain of serially homologous characters, such mammalian molars, evolutionarily "simple." [ABSTRACT FROM AUTHOR]

An enduring problem in biology is explaining how novel functions of genes originated and how those functions diverge between species. Despite detailed studies on the functional evolution of a few proteins, the molecular mechanisms by which protein functions have evolved are almost entirely unknown. Here, we show that a polyalanine tract in the homeodomain transcription factor HoxA11 arose in the stem‐lineage of mammals and functions as an autonomous repressor module by physically interacting with the PAH domains of SIN3 proteins. These results suggest that long polyalanine tracts, which are common in transcription factors and often associated with disease, may tend to function as repressor domains and can contribute to the diversification of transcription factor functions despite the deleterious consequences of polyalanine tract expansion. Research Highlights: A polyalanine track in HoxA11 evolved into a repressor domain through an increase in alanine repeat number, indicating that transcription factors can evolve novel functions despite the potential deleterious consequences associated with amino acid repeats. [ABSTRACT FROM AUTHOR]