The contribution of 7q33 copy number variations for intellectual disability

Copy number variations (CNVs) at the 7q33 cytoband are very rarely described in the literature, and almost all of the cases comprise large deletions affecting more than just the q33 segment. We report seven patients (two families with two siblings and their affected mother and one unrelated patient) with neurodevelopmental delay associated with CNVs in 7q33 alone. All the patients presented mild to moderate intellectual disability (ID), dysmorphic features, and a behavioral phenotype characterized by aggressiveness and disinhibition. One family presents a small duplication in cis affecting CALD1 and AGBL3 genes, while the other four patients carry two larger deletions encompassing EXOC4, CALD1, AGBL3, and CNOT4. This work helps to refine the phenotype and narrow the minimal critical region involved in 7q33 CNVs. Comparison with similar cases and functional studies should help us clarify the relevance of the deleted genes for ID and behavioral alterations.FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the projects PIC/IC/83026/2007, PIC/IC/83013/2007, and POCI-01-0145-FEDER-007038. This work has also been funded by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER)info:eu-repo/semantics/publishedVersio

The Ccr4-Not Complex Interacts with the mRNA Export Machinery

The Ccr4-Not complex is a key eukaryotic regulator of gene transcription and cytoplasmic mRNA degradation. Whether this complex also affects aspects of post-transcriptional gene regulation, such as mRNA export, remains largely unexplored. Human Caf1 (hCaf1), a Ccr4-Not complex member, interacts with and regulates the arginine methyltransferase PRMT1, whose targets include RNA binding proteins involved in mRNA export. However, the functional significance of this regulation is poorly understood.Here we demonstrate using co-immunoprecipitation approaches that Ccr4-Not subunits interact with Hmt1, the budding yeast ortholog of PRMT1. Furthermore, using genetic and biochemical approaches, we demonstrate that Ccr4-Not physically and functionally interacts with the heterogenous nuclear ribonucleoproteins (hnRNPs) Nab2 and Hrp1, and that the physical association depends on Hmt1 methyltransferase activity. Using mass spectrometry, co-immunoprecipitation and genetic approaches, we also uncover physical and functional interactions between Ccr4-Not subunits and components of the nuclear pore complex (NPC) and we provide evidence that these interactions impact mRNA export.Taken together, our findings suggest that Ccr4-Not has previously unrealized functional connections to the mRNA processing/export pathway that are likely important for its role in gene expression. These results shed further insight into the biological functions of Ccr4-Not and suggest that this complex is involved in all aspects of mRNA biogenesis, from the regulation of transcription to mRNA export and turnover

Laboratory tests evaluating the University of South Florida Mobile Data Acquisition System Type 2

Laboratory tests of the University of South Florida Mobile Data Acquisition System, Version 2, were conducted to evaluate accuracy, susceptibility to temperature changes and vibration, and ease of operation. The collected data were also used to test the MDAS data analysis software package XRD11.EXE. Subject to identified accuracy differences and recommended calibration changes, the system is judged adequate. Confirming in-vehicle tests are planned

Factors Affecting the Convergence of Self-Peer Ratings on Contextual and Task Performance

This study examines factors that predict the extent to which 408 operating-level workers rated themselves higher, lower, or the same as their coworkers rated them, for both task and contextual performance. On ratings of contextual performance, underestimators tended to be distinguished by significantly higher levels of both self-monitoring and social desirability. This trend operated similarly, though not significantly for task performance. Additionally, ratings of quantity of work obtained the highest degree of self-peer rating convergence as compared to ratings of quality of work and contextual performance. These results are discussed in terms of the practical implications for multirater systems

The SKP1-Cul1-F-box and Leucine-rich Repeat Protein 4 (SCF-FbxL4) Ubiquitin Ligase Regulates Lysine Demethylase 4A (KDM4A)/Jumonji Domain-containing 2A (JMJD2A) Protein*

Chromatin-modifying enzymes play a fundamental role in regulating chromatin structure so that DNA replication is spatially and temporally coordinated. For example, the lysine demethylase 4A/Jumonji domain-containing 2A (KDM4A/JMJD2A) is tightly regulated during the cell cycle. Overexpression of JMJD2A leads to altered replication timing and faster S phase progression. In this study, we demonstrate that degradation of JMJD2A is regulated by the proteasome. JMJD2A turnover is coordinated through the SKP1-Cul1-F-box ubiquitin ligase complex that contains cullin 1 and the F-box and leucine-rich repeat protein 4 (FbxL4). This complex interacted with JMJD2A. Ubiquitin overexpression restored turnover and blocked the JMJD2A-dependent faster S phase progression in a cullin 1-dependent manner. Furthermore, increased ubiquitin levels decreased JMJD2A occupancy and BrdU incorporation at target sites. This study highlights a finely tuned mechanism for regulating histone demethylase levels and emphasizes the need to tightly regulate chromatin modifiers so that the cell cycle occurs properly

SCFFBXO22 Regulates Histone H3 Lysine 9 and 36 Methylation Levels by Targeting Histone Demethylase KDM4A for Ubiquitin-Mediated Proteasomal Degradation ▿

Reversible methylation of lysine residues has emerged as a central mechanism for epigenetic regulation and is a component of the “histone code,” which engenders histones with gene regulatory information. KDM4A is a histone demethylase that targets tri- and dimethylation marks on histone H3 lysines 9 and 36. While the abundance of KDM4A oscillates in the cell cycle, little is known how this enzyme is regulated to achieve targeted effects on specific histone residues in chromatin. Here, we report that a previously unstudied SCFFBXO22 ubiquitin ligase complex controls the activity of KDM4A by targeting it for proteasomal turnover. FBXO22 functions as a receptor for KDM4A by recognizing its catalytic JmjN/JmjC domains via its intracellular signal transduction (FIST) domain. Modulation of FBXO22 levels by RNA interference or overexpression leads to increased or decreased levels of KDM4A, respectively. Changes in KDM4A abundance correlate with alterations in histone H3 lysine 9 and 36 methylation levels, and transcription of a KDM4A target gene, ASCL2. Taken together, these results demonstrate that SCFFBXO22 regulates changes in histone H3 marks and cognate transcriptional control pathways by controlling KDM4A levels, and they suggest a potential role for FBXO22 in development, differentiation, and disease through spatial and temporal control of KDM4A activity