Emerging Roles for hnRNPs in post-transcriptional regulation: what can we learn from flies?

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a highly conserved family of RNA-binding proteins able to associate with nascent RNAs in order to support their localization, maturation and translation. Research over this last decade has remarked the importance of gene regulatory processes at post-transcriptional level, highlighting the emerging roles of hnRNPs in several essential biological events. Indeed, hnRNPs are key factors in regulating gene expression, thus, having a number of roles in many biological pathways. Moreover, failure of the activities catalysed by hnRNPs affects various biological processes and may underlie several human diseases including cancer, diabetes and neurodegenerative syndromes. In this review, we summarize some of hnRNPs' roles in the model organism Drosophila melanogaster, particularly focusing on their participation in all aspects of post-transcriptional regulation as well as their conserved role and involvement in the aetiology of human pathologies

FSHD muscular dystrophy Region Gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis

Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant myopathy with a strong epigenetic component. It is associated with deletion of a macrosatellite repeat leading to over-expression of the nearby genes. Among them, we focused on FSHD Region Gene 1 (FRG1) since its over-expression in mice, X. laevis and C. elegans leads to muscular dystrophy-like defects, suggesting that FRG1 plays a relevant role in muscle biology. Here we show that, when overexpressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. Moreover, Suv4-20h KO mice develop muscular dystrophy signs. Finally, we identify the FRG1/Suv4-20h1 target Eid3 as a novel myogenic inhibitor that contributes to the muscle differentiation defects. Our study suggests a novel role of FRG1 as epigenetic regulator of muscle differentiation and indicates that Suv4-20h1 has a gene-specific function in myogenesis

Loss of ISWI Function in Drosophila Nuclear Bodies Drives Cytoplasmic Redistribution of Drosophila TDP-43

Over the past decade, evidence has identified a link between protein aggregation, RNA biology, and a subset of degenerative diseases. An important feature of these disorders is the cytoplasmic or nuclear aggregation of RNA-binding proteins (RBPs). Redistribution of RBPs, such as the human TAR DNA-binding 43 protein (TDP-43) from the nucleus to cytoplasmic inclusions is a pathological feature of several diseases. Indeed, sporadic and familial forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration share as hallmarks ubiquitin-positive inclusions. Recently, the wide spectrum of neurodegenerative diseases characterized by RBPs functions' alteration and loss was collectively named proteinopathies. Here, we show that TBPH (TAR DNA-binding protein-43 homolog), the Drosophila ortholog of human TDP-43 TAR DNA-binding protein-43, interacts with the arcRNA hsr omega and with hsr omega-associated hnRNPs. Additionally, we found that the loss of the omega speckles remodeler ISWI (Imitation SWI) changes the TBPH sub-cellular localization to drive a TBPH cytoplasmic accumulation. Our results, hence, identify TBPH as a new component of omega speckles and highlight a role of chromatin remodelers in hnRNPs nuclear compartmentalization

Integrative functional genomic analysis of human brain development and neuropsychiatric risks

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics.We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks

Integrative functional genomic analysis of human brain development and neuropsychiatric risks

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics.We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks

Intra-aortic balloon pump-induced pulsatile flow reduces coagulative and fibrinolytic response to cardiopulmonary bypass

The aim of this study is to evaluate if a simple intra-aortic balloon pump (IABP)-induced pulsatile perfusion reduces activation of coagulative system during cardiopulmonary bypass (CPB). Ninety-six patients undergoing preoperative IABP were randomized to nonpulsatile CPB with IABP discontinued during cardioplegic arrest (Group A) or IABP-induced pulsatile CPB (Group B). White blood cells (WBC), hematocrit (Ht), platelets (PLTs), International Normalized Ratio (INR), fibrinogen, activated partial thromboplastin time (aPTT), antithrombin III (AT-III) activity, and D-dimer were measured at the end of surgery (ES) and postoperatively. Chest drainage, need for reexploration, and transfusions were compared. Group B showed lower chest drainage (1st day P = 0.038; 2nd day P = 0.044), transfusions (P = 0.031), WBC (P < 0.05 at all time points), and INR (P < 0.05 at all time points), together with a higher Ht (P < 0.05 at ES, 12 h), platelets (P < 0.04 at all time points), fibrinogen (P < 0.05 at ES, 12 h, 24 h), and aPTT (P < 0.05 at all time points). AT-III activity lowered in Group A (P = 0.001 at ES, 12 h, 24 h), together with higher D-dimer levels (P < 0.05 at all time points). IABP-induced pulsatile perfusion ameliorates coagulative system activation following CPB