Insight into HOTAIR structural features and functions as landing pads for transcription regulation proteins.

LncRNAs fulfill a wide range of regulatory functions at almost every process of gene expression. While derived from secondary structural features, lncRNAs may function as landing pads for transcription factors (TFs). In this paper, we detected the global structural landscape of 20,338 lncRNAs by utilizing a free energy minimization (MFE) algorithm, and identified the interactions between lncRNAs and TFs to analyze molecular association induced by the lncRNA structure. The accessibility analysis of full sequences as well as potential TF-binding fragments shows a large percentage of structural flanking sequence around the TF binding sites. This investigations paid great attention to the high-order architecture of HOTAIR lncRNA, and identified two coincident modular domains covering fragments 171-410bp and 811-1520bp via RNA-TF association predicting and in-silico computation mining. Then, the structural domains were implied potential landing pads to recruit regulatory proteins (13 TFs) and mediated coordinate regulation of transcription. Pathways and diseases enrichment analysis illustrated that the interacted TFs are significantly Pan-cancer relevant which is consistent with the known function of HOTAIR. Overall, the in-depth understanding of HOTAIR structure provides the first glimpse of coordinate regulation driven by modular features. The detailed architectural context could yield broad biological insights and provides a framework for comprehending lncRNA structure-function interrelationships.

[1]  Hui Zhou,et al.  ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data , 2012, Nucleic Acids Res..

[2]  Alexander Churkin,et al.  Free energy minimization to predict RNA secondary structures and computational RNA design. , 2015, Methods in molecular biology.

[3]  S. Safe,et al.  HOTAIR IS A NEGATIVE PROGNOSTIC FACTOR AND EXHIBITS PRO-ONCOGENIC ACTIVITY IN PANCREATIC CANCER , 2012, Oncogene.

[4]  David H. Mathews,et al.  RNAstructure: software for RNA secondary structure prediction and analysis , 2010, BMC Bioinformatics.

[5]  C. Ponting,et al.  Evolution and Functions of Long Noncoding RNAs , 2009, Cell.

[6]  Yann Ponty,et al.  VARNA: Interactive drawing and editing of the RNA secondary structure , 2009, Bioinform..

[7]  Pierre Baldi,et al.  Assessing the accuracy of prediction algorithms for classification: an overview , 2000, Bioinform..

[8]  Vasant Honavar,et al.  Predicting RNA-Protein Interactions Using Only Sequence Information , 2011, BMC Bioinformatics.

[9]  Howard Y. Chang,et al.  Understanding the transcriptome through RNA structure , 2011, Nature Reviews Genetics.

[10]  P. Clote,et al.  Structural RNA has lower folding energy than random RNA of the same dinucleotide frequency. , 2005, RNA.

[11]  Federico Agostini,et al.  Predicting protein associations with long noncoding RNAs , 2011, Nature Methods.

[12]  Terrence S. Furey,et al.  The UCSC Genome Browser Database , 2003, Nucleic Acids Res..

[13]  James B. Brown,et al.  Long noncoding RNAs are rarely translated in two human cell lines , 2012, Genome research.

[14]  J. Ebel,et al.  Probing the structure of RNAs in solution. , 1987, Nucleic acids research.

[15]  Qiangfeng Cliff Zhang,et al.  Landscape and variation of RNA secondary structure across the human transcriptome , 2014, Nature.

[16]  Howard Y. Chang,et al.  Genome-wide measurement of RNA secondary structure in yeast , 2010, Nature.

[17]  Howard Y. Chang,et al.  Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes , 2010, Science.

[18]  Sean R. Eddy,et al.  Rfam: an RNA family database , 2003, Nucleic Acids Res..

[19]  J. Sabina,et al.  Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure. , 1999, Journal of molecular biology.

[20]  María Martín,et al.  Ongoing and future developments at the Universal Protein Resource , 2010, Nucleic Acids Res..

[21]  Michael P Snyder,et al.  SeqFold: Genome-scale reconstruction of RNA secondary structure integrating high-throughput sequencing data , 2013, Genome research.

[22]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[23]  Michael Zuker,et al.  Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information , 1981, Nucleic Acids Res..

[24]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[25]  Alfonso Mondragón,et al.  Emerging structural themes in large RNA molecules. , 2011, Current opinion in structural biology.

[26]  Eric Westhof,et al.  The Dynamic Landscapes of RNA Architecture , 2009, Cell.

[27]  Antoine M. van Oijen,et al.  Real-time single-molecule observation of rolling-circle DNA replication , 2009, Nucleic acids research.

[28]  J. Doudna,et al.  Insights into RNA structure and function from genome-wide studies , 2014, Nature Reviews Genetics.

[29]  J. Mattick,et al.  Structure and function of long noncoding RNAs in epigenetic regulation , 2013, Nature Structural &Molecular Biology.

[30]  Bronwen L. Aken,et al.  GENCODE: The reference human genome annotation for The ENCODE Project , 2012, Genome research.

[31]  Anna Marie Pyle,et al.  HOTAIR forms an intricate and modular secondary structure. , 2015, Molecular cell.

[32]  Ram Samudrala,et al.  Mouse transcriptome: Neutral evolution of ‘non-coding’ complementary DNAs , 2004, Nature.