Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy

Conti, Anna; Fabbrini, F.; D’Agostino, Pierpaolo; Negri, Rosa; Greco, Dario; Genesio, Rita; D’Armiento, Maria; Olla, Carlo; Paladini, D.; Zannini, Mariastella; Nitsch, Lucio

doi:10.1186/1471-2164-8-268

Cited by 131 publications

(135 citation statements)

References 61 publications

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“…Consistent with our observation that MeCP2 is underexpressed in DS brain specimens, other investigators performing mRNA expression survey experiments utilizing RNA isolated from DS fetal fibroblasts and hearts demonstrated that, although a large number of Hsa21 genes were consistently overexpressed, many non-Hsa21 genes were underexpressed, including MeCP2 (50,51). Additionally, Nagarajan et al (52) demonstrated that the MeCP2 protein was underexpressed in several DS frontal cortex samples.…”

Section: Discussionsupporting

confidence: 89%

Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains

Kuhn

Nuovo

Terry

et al. 2010

Journal of Biological Chemistry

100

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Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype. We demonstrate by luciferase/target mRNA 3-untranslated region reporter assays, and gain-and lossof-function experiments that miR-155 and -802 can regulate the expression of the predicted mRNA target, the methyl-CpG-binding protein (MeCP2). We also demonstrate that MeCP2 is underexpressed in DS brain specimens isolated from either humans or mice. We further demonstrate that, as a consequence of attenuated MeCP2 expression, transcriptionally activated and silenced MeCP2 target genes, CREB1/Creb1 and MEF2C/Mef2c, are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous miR-155 or -802, by antagomir intraventricular injection, resulted in the normalization of MeCP2 and MeCP2 target gene expression. Taken together, these results suggest that improper repression of MeCP2, secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.The presence of three copies of all, or part, of human chromosome 21 (Hsa21) 2 results in the constellation of physiologic traits known as Down syndrome (DS) or Trisomy 21 (1).With an incidence of approximately one in 750 live births, DS is the most frequently survivable congenital chromosomal abnormality (2, 3). The phenotypes of DS are complex and variable; they include cognitive impairment, congenital heart defects, craniofacial abnormalities, gastrointestinal anomalies, leukemia, and Alzheimer disease (1-3). Experimental studies utilizing tissues derived from individuals with DS have confirmed that expression of trisomic genes is increased by ϳ50% (i.e. consistent with gene dosage) (4 -6). Recent bioinformatic annotation has established that Hsa21 harbors more than 500 genes (7, 8), including five miRNA genes (miR-99a, let-7c, miR125b-2, miR-155, and miR-802). miRNAs are a family of small, ϳ21-nucleotide long, nonprotein-coding RNAs that have emerged as key post-transcriptional regulators of gene expression (9 -11). miRNAs are processed from precursor molecules (pri-miRNAs), which are either transcribed from independent miRNA genes or are portions of introns of protein-coding RNA polymerase II transcripts. Following their processing, miRNAs are assembled into ribonucleoprotein complexes called microribonucleoproteins (miRNPs) or miRNA-...

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Section: Discussionsupporting

confidence: 89%

Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains

Kuhn

Nuovo

Terry

et al. 2010

Journal of Biological Chemistry

100

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“…Second, we used fetal fibroblasts from DS subjects as a possible natural model for CAML-WRB imbalance. Indeed, WRB is encoded in a gene on chromosome 21, and previous studies demonstrated that its transcript is among those that are 1.5-fold up-regulated in DS cells (39,40); however, WRB protein levels had not been investigated up till now. We found that in primary fibroblasts, WRB protein is up-regulated similarly to its transcript, resulting in a ϳ1.5-fold increased ratio of WRB to CAML.…”

Section: Discussionmentioning

confidence: 99%

“…The WRB gene is located in the distal region of the long arm of chromosome 21 (Hsa21), in a region thought to play a critical role in the Down syndrome (DS) phenotype (DS critical region) (38). WRB is among the Hsa21 transcripts reported to be 1.5-fold up-regulated in trisomic fibroblasts (39) and in DS fetal heart (40).…”

Section: Imbalance Of Caml-wrb Stoichiometry Does Notmentioning

confidence: 99%

Tail-anchored Protein Insertion in Mammals

Colombo

Cardani

Maroli

et al. 2016

Journal of Biological Chemistry

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The GET (guided entry of tail-anchored proteins)/TRC (transmembrane recognition complex) pathway for tail-anchored protein targeting to the endoplasmic reticulum (ER) has been characterized in detail in yeast and is thought to function similarly in mammals, where the orthologue of the central ATPase, Get3, is known as TRC40 or Asna1. Get3/TRC40 function requires an ER receptor, which in yeast consists of the Get1/ Get2 heterotetramer and in mammals of the WRB protein (tryptophan-rich basic protein), homologous to yeast Get1, in combination with CAML (calcium-modulating cyclophilin ligand), which is not homologous to Get2. To better characterize the mammalian receptor, we investigated the role of endogenous WRB and CAML in tail-anchored protein insertion as well as their association, concentration, and stoichiometry in rat liver microsomes and cultured cells. Functional proteoliposomes, reconstituted from a microsomal detergent extract, lost their activity when made with an extract depleted of TRC40-associated proteins or of CAML itself, whereas in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes. CAML was found to be in ϳ5-fold excess over WRB, and alteration of this ratio did not inhibit insertion. Depletion of each subunit affected the levels of the other one; in the case of CAML silencing, this effect was attributable to destabilization of the WRB transcript and not of WRB protein itself. These results reveal unanticipated complexity in the mutual regulation of the TRC40 receptor subunits and raise the question as to the role of the excess CAML in the mammalian ER.Whereas most membrane proteins are targeted to the endoplasmic reticulum (ER) 3 by the signal recognition particle-dependent co-translational mechanism (1, 2), tail-anchored (TA) membrane proteins are inserted into all their target membranes, including the ER, by post-translational pathways (for review see Refs. 3-5). The inability of TA proteins to utilize the co-translational route is due to the location of their sole targeting determinant, the transmembrane domain (TMD), at their extreme C terminus, such that it becomes accessible to cytosolic targeting factors only after release of the completed polypeptide chain from the ribosome. Because TA proteins are numerous (6), play fundamental physiological roles (e.g. as SNAREs and apoptosis regulating factors; Ref.3), and are present in all domains of life (7), a great deal of research has been dedicated to the elucidation of the mechanisms by which they reach and insert into their target membranes. On the basis of studies in cell-free mammalian systems (8, 9) and of in vitro and in vivo investigations in yeast (10), a novel system operating in the delivery of TA proteins to the ER membrane was identified and extensively characterized (for review, see Refs. 11 and 12). This system is centered around a cytosolic P-type ATPase, named Get3 (guided entry of tailanchored proteins) in yeast and TRC40 (transmembrane domain recognition complex subunit of 40...

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“…GSE1789) was recruited. GSE1789 comprised a total of 15 samples, including 10 samples from fetuses trisomic for Hsa21 and 5 from euploid normal control fetuses (Conti et al, 2007). The expression profile also existed on the Affymetrix GeneChip Human Genome U133A Platform.…”

Section: Gene Expression Data Recruitmentmentioning

confidence: 99%

“…Recent studies have also suggested the potential contribution of VEGFA (Ackerman et al, 2012), cleome and Hedgehog (Ripoll et al, 2012), and folate (Locke et al, 2010) pathways to the pathogenicity of DS-CHD. The transcription profile of DS-CHD was obtained based on the Hsa21 genes in the heart of 18-22-week-old human fetuses (Conti et al, 2007). However, the underlying contribution of the variations in gene expression to the incidence of DS-CHD remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

Yq¹,

T²,

Wy³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to identify disrupted pathways related to Down syndrome (DS), and DS-associated congenital heart defects (DS-CHD). The gene expression profile and pathway data of 10 human DS patients and 5 control samples in E-GEOD-1789 were recruited and analyzed by the individualized pathway aberrance score (iPAS) method, consisting of the data processing, gene-level statistics, pathway-level statistics, and significant measurement steps. The pre-processing step identified 12,493 genes and 1022 pathways (4269 genes). The pathway significant analysis identified eight pathways (adjusted P value <0.1) that differed between the disease and control samples. The cross-presentation of particulate exogenous antigen (phagosomes) and methionine salvage pathways showed the most significant differences among these. The gene expression levels of key pathway genes, such as CYBB and ADI1, were higher in disease samples than in normal controls. Based on our results, we predicted that the cross-presentation of particulate exogenous antigens (phagosomes) and the methionine salvage pathway could be good indicators of DS-CHD.

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Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy

Cited by 131 publications

References 61 publications

Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains

Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains

Tail-anchored Protein Insertion in Mammals

Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

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