The Case of the Fickle Fingers: How the PRDM9 Zinc Finger Protein Specifies Meiotic Recombination Hotspots in Humans

Recent discoveries have revealed the central role of PRDM9 in mammalian recombination. The precise function of this protein, however, remains poorly understood, as do the causes for its rapid evolution and its role in reproductive isolation

HoxA-11 and FOXO1A Cooperate to Regulate Decidual Prolactin Expression: Towards Inferring the Core Transcriptional Regulators of Decidual Genes

During the menstrual cycle, the ovarian steroid hormones estrogen and progesterone control a dramatic transcriptional reprogramming of endometrial stromal cells (ESCs) leading to a receptive state for blastocyst implantation and the establishment of pregnancy. A key marker gene of this decidualization process is the prolactin gene. Several transcriptional regulators have been identified that are essential for decidualization of ESCs, including the Hox genes HoxA-10 and HoxA-11, and the forkhead box gene FOXO1A. While previous studies have identified downstream target genes for HoxA-10 and FOXO1A, the role of HoxA-11 in decidualization has not been investigated. Here, we show that HoxA-11 is required for prolactin expression in decidualized ESC. While HoxA-11 alone is a repressor on the decidual prolactin promoter, it turns into an activator when combined with FOXO1A. Conversely, HoxA-10, which has been previously shown to associate with FOXO1A to upregulate decidual IGFBP-1 expression, is unable to upregulate PRL expression when co-expressed with FOXO1A. By co-immunoprecipitation and chromatin immunoprecipitation, we demonstrate physical association of HoxA-11 and FOXO1A, and binding of both factors to an enhancer region (−395 to −148 relative to the PRL transcriptional start site) of the decidual prolactin promoter. Because FOXO1A is induced upon decidualization, it serves to assemble a decidual-specific transcriptional complex including HoxA-11. These data highlight cooperativity between numerous transcription factors to upregulate PRL in differentiating ESC, and suggest that this core set of transcription factors physically and functionally interact to drive the expression of a gene battery upregulated in differentiated ESC. In addition, the functional non-equivalence of HoxA-11 and HoxA-10 with respect to PRL regulation suggests that these transcription factors regulate distinct sets of target genes during decidualization

MyoMiner: explore gene co-expression in normal and pathological muscle

International audienceBackground: High-throughput transcriptomics measures mRNA levels for thousands of genes in a biological sample. Most gene expression studies aim to identify genes that are differentially expressed between different biological conditions, such as between healthy and diseased states. However, these data can also be used to identify genes that are co-expressed within a biological condition. Gene co-expression is used in a guilt-by-association approach to prioritize candidate genes that could be involved in disease, and to gain insights into the functions of genes, protein relations, and signaling pathways. Most existing gene co-expression databases are generic, amalgamating data for a given organism regardless of tissue-type.Methods: To study muscle-specific gene co-expression in both normal and pathological states, publicly available gene expression data were acquired for 2376 mouse and 2228 human striated muscle samples, and separated into 142 categories based on species (human or mouse), tissue origin, age, gender, anatomic part, and experimental condition. Co-expression values were calculated for each category to create the MyoMiner database.Results: Within each category, users can select a gene of interest, and the MyoMiner web interface will return all correlated genes. For each co-expressed gene pair, adjusted p-value and confidence intervals are provided as measures of expression correlation strength. A standardized expression-level scatterplot is available for every gene pair r-value. MyoMiner has two extra functions: (a) a network interface for creating a 2-shell correlation network, based either on the most highly correlated genes or from a list of genes provided by the user with the option to include linked genes from the database and (b) a comparison tool from which the users can test whether any two correlation coefficients from different conditions are significantly different.Conclusions: These co-expression analyses will help investigators to delineate the tissue-, cell-, and pathology-specific elements of muscle protein interactions, cell signaling and gene regulation. Changes in co-expression between pathologic and healthy tissue may suggest new disease mechanisms and help define novel therapeutic targets. Thus, MyoMiner is a powerful muscle-specific database for the discovery of genes that are associated with related functions based on their co-expression. MyoMiner is freely available at https://www.sys-myo.com/myominer

Molecular Dynamics of Mesophilic-Like Mutants of a Cold-Adapted Enzyme: Insights into Distal Effects Induced by the Mutations

Networks and clusters of intramolecular interactions, as well as their “communication” across the three-dimensional architecture have a prominent role in determining protein stability and function. Special attention has been dedicated to their role in thermal adaptation. In the present contribution, seven previously experimentally characterized mutants of a cold-adapted α-amylase, featuring mesophilic-like behavior, have been investigated by multiple molecular dynamics simulations, essential dynamics and analyses of correlated motions and electrostatic interactions. Our data elucidate the molecular mechanisms underlying the ability of single and multiple mutations to globally modulate dynamic properties of the cold-adapted α-amylase, including both local and complex unpredictable distal effects. Our investigation also shows, in agreement with the experimental data, that the conversion of the cold-adapted enzyme in a warm-adapted variant cannot be completely achieved by the introduction of few mutations, also providing the rationale behind these effects. Moreover, pivotal residues, which are likely to mediate the effects induced by the mutations, have been identified from our analyses, as well as a group of suitable candidates for protein engineering. In fact, a subset of residues here identified (as an isoleucine, or networks of mesophilic-like salt bridges in the proximity of the catalytic site) should be considered, in experimental studies, to get a more efficient modification of the features of the cold-adapted enzyme

Developing a clinically relevant model of cognitive training after experimental traumatic brain injury.

BACKGROUND: Following traumatic brain injury (TBI), clinical cognitive training paradigms harness implicit and explicit learning and memory systems to improve function; however, these systems are differentially affected by TBI, highlighting the need for an experimental TBI model that can test efficacy of cognitive training approaches. OBJECTIVES: To develop a clinically relevant experimental cognitive training model using the Morris water maze (MWM) wherein training on implicitly learned task components was provided to improve behavioral performance post-TBI. METHODS: Eighty-one adult male rats were divided by injury status (controlled cortical impact [CCI]/Sham), non-spatial cognitive training (CogTrained/No-CogTrained), and extra-maze cues (Cued/Non-Cued) during MWM testing. Platform latencies, thigmotaxis, and search strategies were assessed during MWM trials. RESULTS: Cognitive training was associated with improved platform latencies, reduced thigmotaxis, and more effective search strategy use for Sham and CCI rats. In the Cued and Non-Cued MWM paradigm, there were no differences between CCI/CogTrained and Sham/No-CogTrained groups. During novel testing conditions, CogTrained groups applied implicitly learned knowledge/skills; however, sham-cued CogTrained/rats better incorporated extramaze cues into their search strategy than the CCI-Cued group. Cognitive training had no effects on contusion size or hippocampal cell survival. CONCLUSIONS: The results provide evidence that CCI-CogTrained rats that learned the nonspatial components of the MWM task applied these skills during multiple conditions of the place-learning task, thereby mitigating cognitive deficits typically associated with this injury model. The results show that a systematic application of clinically relevant constructs associated with cognitive training paradigms can be used with experimental TBI to affect place learning