title: Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes.
abstract: 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.
  
  
  CONCLUSIONS
  The presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis.
authors.affiliation: Bioengineering and Bioinformatics Program, Department of Pathology, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX, 77030, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Beck
authors.forename: Steve
authors.initials: S
authors.lastname: Ayers
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wen
authors.forename: Miriam B
authors.initials: MB
authors.lastname: Brandl
authors.forename: Tuan D
authors.initials: TD
authors.lastname: Pham
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Chung-Che
authors.initials: CC
authors.lastname: Chang
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
mesh_terms: D019295:Computational Biology; D005091:Exons; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009690:Nucleic Acid Conformation; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D058727:RNA, Small Untranslated / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic
chemical_list: D058727:RNA, Small Untranslated; D012319:RNA Polymerase II