HELLP babies link a novel lincRNA to the trophoblast cell cycle

The Journal of clinical investigation (Impact Factor: 13.22). 10/2012; 122(11). DOI: 10.1172/JCI65171
Source: PubMed

ABSTRACT The HELLP syndrome is a pregnancy-associated disease inducing hemolysis, elevated liver enzymes, and low platelets in the mother. Although the HELLP symptoms occur in the third trimester in the mother, the origin of the disease can be found in the first trimester fetal placenta. A locus for the HELLP syndrome is present on chromosome 12q23 near PAH. Here, by multipoint nonparametric linkage, pedigree structure allele sharing, and haplotype association analysis of affected sisters and cousins, we demonstrate that the HELLP locus is in an intergenic region on 12q23.2 between PMCH and IGF1. We identified a novel long intergenic noncoding RNA (lincRNA) transcript of 205,012 bases with (peri)nuclear expression in the extravillous trophoblast using strand-specific RT-PCR complemented with RACE and FISH. siRNA-mediated knockdown followed by RNA-sequencing, revealed that the HELLP lincRNA activated a large set of genes that are involved in the cell cycle. Furthermore, blocking potential mutation sites identified in HELLP families decreased the invasion capacity of extravillous trophoblasts. This is the first large noncoding gene to be linked to a Mendelian disorder with autosomal-recessive inheritance.

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Available from: Hari krishna Thulluru, Sep 28, 2015
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    • "While this syndrome represents a mendelian disorder, mapped using a traditional genetic analysis of affected families, the mutations occur in a non-coding region that harbors an ncRNA approximately 200 kb long. Subsequent analysis has shown that mutations can affect stability of this RNA [41], which also functions by trans-regulating hundreds of target genes. "
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    ABSTRACT: In the past decade, numerous studies have made connections between sequence variants in human genomes and predisposition to complex diseases. However, most of these variants lie outside of the charted regions of the human genome whose function we understand; that is, the sequences that encode proteins. Consequently, the general concept of a mechanism that translates these variants into predisposition to diseases has been lacking, potentially calling into question the validity of these studies. Here we make a connection between the growing class of apparently functional RNAs that do not encode proteins and whose function we do not yet understand (the so-called 'dark matter' RNAs) and the disease-associated variants. We review advances made in a different genomic mapping effort - unbiased profiling of all RNA transcribed from the human genome - and provide arguments that the disease-associated variants exert their effects via perturbation of regulatory properties of non-coding RNAs existing in mammalian cells.
    BMC Medicine 06/2014; 12(1):97. DOI:10.1186/1741-7015-12-97 · 7.25 Impact Factor
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    • "DNA methylation, histone modification and non-coding RNA (ncRNA) and the interactions between them are some of the epigenetic mechanisms that have been studied in the placenta (Fuks et al., 2003; Nelissen et al., 2011). The field of epigenetics is continually expanding and there is recent interest in DNA hydroxymethylation and TET methylcytosine dioxygenases (ten-eleven translocation) (Tahiliani et al., 2009; Dahl et al., 2011; Xu et al., 2011; Zhao and Chen, 2013), and the role of various types of ncRNA, such as micro RNAs (miRNA) (Tsai et al., 2009; Ji et al., 2013; Mouillet et al., 2013) and long intergenic ncRNA (lincRNA) (van Dijk et al., 2012). The three main DNMTs that methylate cytosines in CpG dinucleotides to 5-methylcytosine (5mC) are DNMT1, the maintenance methyltransferase, and the de novo methyltransferases DNMT3A and DNMT3B, which each have gene-specific methylation sites in distinct genomic DNA regions (Hsieh, 1999; Okano et al., 1999; Takeshima et al., 2006). "
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    ABSTRACT: Specialized cell types of trophoblast cells form the placenta in which each cell type has particular properties of proliferation and invasion. The placenta sustains the growth of the fetus throughout pregnancy and any aberrant trophoblast differentiation or invasion potentially affects the future health of the child and adult. Recently, the field of epigenetics has been applied to understand differentiation of trophoblast lineages and embryonic stem cells (ESC), from fertilization of the oocyte onward. Each trophoblast cell-type has a distinctive epigenetic profile and we will concentrate on the epigenetic mechanism of DNA methyltransferases and TETs that regulate DNA methylation. Environmental factors affecting the mother potentially regulate the DNA methyltransferases in trophoblasts, and so do steroid hormones, cell cycle regulators, such as p53, and cytokines, especially interlukin-1β. There are interesting questions of why trophoblast genomes are globally hypomethylated yet specific genes can be suppressed by hypermethylation (in general, tumor suppressor genes, such as E-cadherin) and how invasive cell-types are liable to have condensed chromatin, as in metastatic cancer cells. Future work will attempt to understand the interactive nature of all epigenetic mechanisms together and their effect on the complex biological system of trophoblast differentiation and invasion in normal as well as pathological conditions.
    Frontiers in Genetics 12/2013; 4:265. DOI:10.3389/fgene.2013.00265
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    • "This indicated that pre-eclampsia and the HELLP-syndrome are different genetic entities. The chromosomal linkage associated with the HELLP-syndrome has recently been found to be located on chromosome 12q23 (Van Dijk et al., 2012). Here, a long non-coding RNA (205 kb) has been identified that is expressed in extravillous trophoblasts of first trimester placenta. "
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    ABSTRACT: This review describes the current knowledge regarding genetics and epigenetics of pregnancy-associated diseases with placental origin. We discuss the effect on genetic linkage analyses when the fetal genotype determines the maternal phenotype. Secondly, the genes identified by genome-wide linkage studies to be associated with pre-eclampsia (ACVR2A, STOX1) and the HELLP-syndrome (LINC-HELLP) are discussed regarding their potential functions in the etiology of disease. Furthermore, susceptibility genes identified by candidate gene approaches (e.g., CORIN) are described. Next, we focus on the additional challenges that come when epigenetics also play a role in disease inheritance. We discuss the maternal transmission of the chromosome 10q22 pre-eclampsia linkage region containing the STOX1 gene and provide further evidence for the role of epigenetics in pre-eclampsia based on the cdkn1c mouse model of pre-eclampsia. Finally, we provide recommendations to unravel the genetics of pregnancy-associated diseases, specifically regarding clear definitions of patient groups and sufficient patient numbers, and the potential usefulness of (epi)genetic data in early non-invasive biomarker development.
    Frontiers in Genetics 09/2013; 4:180. DOI:10.3389/fgene.2013.00180
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