Chromatin structure analyses identify miRNA promoters

  1. Fatih Ozsolak1,2,
  2. Laura L. Poling1,2,
  3. Zhengxin Wang3,
  4. Hui Liu4,
  5. X. Shirley Liu5,6,
  6. Robert G. Roeder7,
  7. Xinmin Zhang4,
  8. Jun S. Song8,10, and
  9. David E. Fisher1,2,9
  1. 1 Department of Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
  2. 2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02114, USA;
  3. 3 The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
  4. 4 Roche NimbleGen, Inc., Madison, Wisconsin 53719, USA;
  5. 5 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
  6. 6 Harvard School of Public Health, Boston, Massachusetts 02115, USA;
  7. 7 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10021, USA;
  8. 8 The Simons Center for Systems Biology, Institute for Advanced Study, Einstein Drive, Princeton, New Jersey 08540, USA

Abstract

Although microRNAs (miRNAs) are key regulators of gene expression in normal human physiology and disease, transcriptional regulation of miRNAs is poorly understood, because most miRNA promoters have not yet been characterized. We identified the proximal promoters of 175 human miRNAs by combining nucleosome mapping with chromatin signatures for promoters. We observe that one-third of intronic miRNAs have transcription initiation regions independent from their host promoters and present a list of RNA polymerase II- and III-occupied miRNAs. Nucleosome mapping and linker sequence analyses in miRNA promoters permitted accurate prediction of transcription factors regulating miRNA expression, thus identifying nine miRNAs regulated by the MITF transcription factor/oncoprotein in melanoma cells. Furthermore, DNA sequences encoding mature miRNAs were found to be preferentially occupied by positioned-nucleosomes, and the 3′ end sites of known genes exhibited nucleosome depletion. The high-throughput identification of miRNA promoter and enhancer regulatory elements sheds light on evolution of miRNA transcription and permits rapid identification of transcriptional networks of miRNAs.

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