Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes.

Dominik Beck,Paul Webb,Chung-Che Chang,Xiaobo Zhou,Steve Ayers,Tuan D Pham,Miriam B Brandl,Jianguo Wen

doi:10.1186/1755-8794-4-19

Dominik Beck, Paul Webb + Show 6 more

Open Access

https://doi.org/10.1186/1755-8794-4-19

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Abstract

BackgroundMyelodysplastic 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.MethodsPatients' 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.ResultsIn 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.DiscussionThe presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis.

Highlights

Myelodysplastic Syndromes (MDSS) are pre-leukemic disorders with increasing incident rates worldwide, but very limited treatment options
In this paper we presented the first systematic profiling for small RNAs in Myelodysplastic Syndromes using generation sequencing on the current Illumina Genome Analyzer IIx platform
The analysis showed that the small RNAome in low-grade MDS (RA) was enriched for Piwi interacting RNAs (piRNA), potentially protecting DNA from the accumulation of mutations, a mechanism not observed in high-grade MDS (RAEB2)

Summary

Introduction

Myelodysplastic Syndromes (MDSS) are pre-leukemic disorders with increasing incident rates worldwide, but very limited treatment options. Myelodysplastic Syndromes (MDS) are a group of heterogeneous hematopoietic stem cell disorders, which often lead to acute myeloid leukemia (AML). This group of diseases is most common in the growing demographic of the late sixties-early seventies [1]. Patients can be classified into risk groups, primarily based on bone marrow myeloblast counts [3,4]. These include refractory anemia (RA), describing an early disease stage (low-grade MDS) and the refractory anemias with excess of blasts (RAEB1, RAEB2), which represent the later stages of the disease (high-grade MDS). They mainly include allogeneic stem cell transplantation, treatment with hypomethylating agents and Lenalidomide

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