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Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes
Bioengineering and Bioinformatics Program, The Methodist Hospital Research Institute, Weill Cornell Medical College, USA//The University of New South Wales, Canberra, ACT, 2600, Australia..
Department of Pathology, The Methodist Hospital and The Methodist.
The Methodist Hospital and The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX, USA.
Bioengineering and Bioinformatics Program, The Methodist Hospital Research Institute, Weill Cornell Medical College, USA//The University of New South Wales, Canberra, ACT, 2600, Australia..
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2011 (Engelska)Ingår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 4, nr 19, s. 1-16Artikel i tidskrift (Refereegranskat) Published
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Abstract [en]

Background

Myelodysplastic Syndromes (MDSS) are pre-leukemic disorders with increasing incident rates worldwide, but very limited treatment options. Little is known about small regulatory RNAs and how they contribute to pathogenesis, progression and transcriptome changes in MDS.

Methods

Patients' primary marrow cells were screened for short RNAs (RNA-seq) using next generation sequencing. Exon arrays from the same cells were used to profile gene expression and additional measures on 98 patients obtained. Integrative bioinformatics algorithms were proposed, and pathway and ontology analysis performed.

Results

In low-grade MDS, observations implied extensive post-transcriptional regulation via microRNAs (miRNA) and the recently discovered Piwi interacting RNAs (piRNA). Large expression differences were found for MDS-associated and novel miRNAs, including 48 sequences matching to miRNA star (miRNA*) motifs. The detected species were predicted to regulate disease stage specific molecular functions and pathways, including apoptosis and response to DNA damage. In high-grade MDS, results suggested extensive post-translation editing via transfer RNAs (tRNAs), providing a potential link for reduced apoptosis, a hallmark for this disease stage. Bioinformatics analysis confirmed important regulatory roles for MDS linked miRNAs and TFs, and strengthened the biological significance of miRNA*. The "RNA polymerase II promoters" were identified as the tightest controlled biological function. We suggest their control by a miRNA dominated feedback loop, which might be linked to the dramatically different miRNA amounts seen between low and high-grade MDS.

Discussion

The presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis.

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2011. Vol. 4, nr 19, s. 1-16
Nationell ämneskategori
Medicinsk genetik
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URN: urn:nbn:se:liu:diva-127826DOI: 10.1186/1755-8794-4-19OAI: oai:DiVA.org:liu-127826DiVA, id: diva2:928879
Tillgänglig från: 2016-05-17 Skapad: 2016-05-13 Senast uppdaterad: 2018-01-10

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