title: Genomic features and computational identification of human microRNAs under long-range developmental regulation.
abstract: BACKGROUND
  Recent functional studies have demonstrated that many microRNAs (miRNAs) are expressed by RNA polymerase II in a specific spatiotemporal manner during the development of organisms and play a key role in cell-lineage decisions and morphogenesis. They are therefore functionally related to a number of key protein coding developmental genes, that form genomic regulatory blocks (GRBs) with arrays of highly conserved non-coding elements (HCNEs) functioning as long-range enhancers that collaboratively regulate the expression of their target genes. Given this functional similarity as well as recent zebrafish transgenesis assays showing that the miR-9 family is indeed regulated by HCNEs with enhancer activity, we hypothesized that this type of miRNA regulation is prevalent. In this paper, we therefore systematically investigate the regulatory landscape around conserved self-transcribed miRNAs (ST miRNAs), with their own known or computationally inferred promoters, by analyzing the hallmarks of GRB target genes. These include not only the density of HCNEs in their vicinity but also the presence of large CpG islands (CGIs) and distinct patterns of histone modification marks associated with developmental genes.
  
  
  RESULTS
  Our results show that a subset of the conserved ST miRNAs we studied shares properties similar to those of protein-coding GRB target genes: they are located in regions of significantly higher HCNE/enhancer binding density and are more likely to be associated with CGIs. Furthermore, their putative promoters have both activating as well as silencing histone modification marks during development and differentiation. Based on these results we used both an elevated HCNE density in the genomic vicinity as well as the presence of a bivalent promoter to identify 29 putative GRB target miRNAs/miRNA clusters, over two-thirds of which are known to play a role during development and differentiation. Furthermore these predictions include miRNAs of the miR-9 family, which are the only experimentally verified GRB target miRNAs.
  
  
  CONCLUSIONS
  A subset of the conserved miRNA loci we investigated exhibits typical characteristics of GRB target genes, which may partially explain their complex expression profiles during development.
authors: Computational Biology Unit, Bergen Center for Computational Science, and Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, 5008, Norway. Ying.Sheng@medisin.uio.no
authors: Ying
authors: Y
authors: Sheng
authors: Christopher
authors: C
authors: Previti
references: Cancer Cell. 2008 Nov 4;14(5):369-81
references: 18977326
references: Nat Struct Mol Biol. 2006 Dec;13(12):1097-101
references: 17099701
references: Development. 2006 Feb;133(4):761-72
references: 16407397
references: FEBS J. 2009 Nov;276(22):6509-21
references: 20102393
references: Cell. 1998 May 1;93(3):361-72
references: 9590171
references: J Lipid Res. 2010 Jun;51(6):1513-23
references: 20124555
references: OMICS. 2009 Dec;13(6):513-20
references: 19780683
references: Med Mol Morphol. 2009 Jun;42(2):102-9
references: 19536617
references: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5521-6
references: 17376869
references: Neuron. 2007 Jun 7;54(5):813-29
references: 17553428
references: Reprod Sci. 2008 Dec;15(10):993-1001
references: 19088369
references: Fen Zi Xi Bao Sheng Wu Xue Bao. 2008 Oct;41(5):341-8
references: 19127769
references: Genome Res. 2007 May;17(5):545-55
references: 17387144
references: Mol Endocrinol. 2009 Feb;23(2):265-75
references: 19074548
references: Bioessays. 2006 May;28(5):445-8
references: 16615131
references: J Biol Chem. 2007 Jan 26;282(4):2130-4
references: 17135268
references: Neuroreport. 2007 Feb 12;18(3):297-300
references: 17314675
references: Cell Res. 2008 Oct;18(10):985-96
references: 18711447
references: Genes Dev. 2008 Nov 15;22(22):3172-83
references: 19056895
references: PLoS Biol. 2005 Jan;3(1):e7
references: 15630479
references: Cell Stem Cell. 2007 Sep 13;1(3):299-312
references: 18371364
references: Mol Cell. 1998 Jan;1(2):277-87
references: 9659924
references: Oncogene. 2008 Jan 10;27(3):378-86
references: 17621267
references: Clin Cancer Res. 2009 Oct 1;15(19):6192-200
references: 19789312
references: Dev Biol. 2009 Mar 15;327(2):526-40
references: 19073165
references: Nature. 2006 Nov 23;444(7118):499-502
references: 17086198
references: Genes Dev. 1996 Oct 1;10(19):2478-90
references: 8843199
references: Platelets. 2009 Sep;20(6):391-400
references: 19811223
references: PLoS One. 2009;4(4):e5033
references: 19343226
references: Cell Res. 2008 May;18(5):549-57
references: 18379589
references: Nucleic Acids Res. 2008 Jan;36(Database issue):D5-12
references: 18039715
references: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16230-5
references: 18852463
references: PLoS One. 2008 May 14;3(5):e2141
references: 18478077
references: Immunity. 2009 Dec 18;31(6):965-73
references: 20005135
references: Nature. 2007 Aug 2;448(7153):553-60
references: 17603471
references: Stem Cells. 2006 Apr;24(4):857-64
references: 16357340
references: Genome Res. 2005 Aug;15(8):1061-72
references: 16024824
references: Hepatology. 2010 May;51(5):1494-504
references: 20127796
references: Mol Cell. 2007 Jun 8;26(5):745-52
references: 17540599
references: Genome Res. 2010 May;20(5):589-99
references: 20439436
references: BMC Med. 2008 Jun 24;6:14
references: 18577219
references: Mamm Genome. 2006 Oct;17(10):1033-41
references: 17019647
references: Nucleic Acids Res. 2008 Jan;36(Database issue):D154-8
references: 17991681
references: Mol Cell. 2009 Oct 9;36(1):61-74
references: 19818710
references: Biochim Biophys Acta. 2008 Nov;1779(11):697-701
references: 18655850
references: Biochem Biophys Res Commun. 2009 Mar 13;380(3):437-41
references: 19284987
references: Cell. 2006 Apr 21;125(2):315-26
references: 16630819
references: Cell Stem Cell. 2008 Mar 6;2(3):219-29
references: 18371447
references: BMC Genomics. 2008 May 21;9:236
references: 18492288
references: RNA. 2004 Oct;10(10):1586-94
references: 15337850
references: Nature. 2008 Mar 13;452(7184):225-9
references: 18311128
references: Genome Biol. 2009;10(4):R38
references: 19374772
references: Clin Cancer Res. 2009 Apr 15;15(8):2850-5
references: 19351747
references: Bioessays. 2005 Sep;27(9):937-45
references: 16108068
references: Biochem Biophys Res Commun. 2010 May 28;396(2):501-7
references: 20420807
references: Int J Cancer. 2009 Dec 1;125(11):2737-43
references: 19521961
references: BMC Genomics. 2008 Nov 27;9:564
references: 19038026
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D557-62
references: 19906699
references: Genes Dev. 1994 Apr 15;8(8):869-84
references: 7523245
references: Leukemia. 2009 Feb;23(2):313-22
references: 18923441
references: J Cereb Blood Flow Metab. 2010 Apr;30(4):744-56
references: 20010955
references: RNA. 2005 Aug;11(8):1245-57
references: 15987809
references: Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21179-84
references: 19965369
references: Cancer Res. 2010 Jan 1;70(1):36-45
references: 20028859
references: Curr Opin Neurobiol. 2009 Oct;19(5):461-70
references: 19846291
references: Neuron. 2010 Feb 11;65(3):373-84
references: 20159450
references: Stem Cells Dev. 2010 Jan;19(1):17-26
references: 19435428
references: Dev Biol. 2009 Oct 15;334(2):468-80
references: 19682983
references: EMBO J. 2004 Oct 13;23(20):4051-60
references: 15372072
references: Cancer Res. 2007 Oct 15;67(20):9762-70
references: 17942906
references: Cancer Res. 2009 Jul 15;69(14):5776-83
references: 19584273
references: Hepatology. 2008 Jun;47(6):1955-63
references: 18433021
references: Genome Biol. 2009;10(8):R86
references: 19698106
references: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
references: 12434020
references: Nat Genet. 2007 Mar;39(3):311-8
references: 17277777
references: J Dig Dis. 2009 Aug;10(3):188-94
references: 19659786
references: Cancer Res. 2008 Mar 1;68(5):1362-8
references: 18316599
references: Int J Oncol. 2009 Feb;34(2):537-42
references: 19148490
references: Carcinogenesis. 2010 Feb;31(2):252-8
references: 19748927
references: Hippocampus. 2010 Apr;20(4):492-8
references: 19557767
references: Cell Transplant. 2009;18(9):1039-45
references: 19523330
references: Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17719-24
references: 17965236
references: Cell Death Differ. 2010 Feb;17(2):209-14
references: 19461655
references: Annu Rev Genomics Hum Genet. 2006;7:29-59
references: 16719718
references: Clin Genet. 2008 Oct;74(4):296-306
references: 18713256
references: Nature. 2009 Feb 12;457(7231):854-8
references: 19212405
references: BMC Genomics. 2004 Dec 21;5(1):99
references: 15613238
references: Cancer Res. 2009 Jun 1;69(11):4851-60
references: 19487295
references: RNA. 2004 Dec;10(12):1957-66
references: 15525708
references: Genome Res. 2005 Jul;15(7):928-35
references: 15965026
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D755-61
references: 18996895
references: BMC Genomics. 2006 Feb 15;7:25
references: 16480513
references: Genome Biol. 2008;9(2):R34
references: 18279518
references: J Pathol. 2010 Jan;220(1):71-86
references: 19768731
references: Mol Cell Endocrinol. 2009 Apr 10;302(1):12-7
references: 19356622
references: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18610-5
references: 19846767
references: Clin Cancer Res. 2010 Feb 15;16(4):1129-39
references: 20145181
references: Dev Biol. 2010 Jan 15;337(2):484-95
references: 19850031
references: Exp Hematol. 2007 Apr;35(4):551-64
references: 17379065
references: Genes Dev. 2007 Apr 1;21(7):744-9
references: 17403776
references: Carcinogenesis. 2009 Dec;30(12):2059-63
references: 19901002
references: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12481-6
references: 16885212
references: PLoS Comput Biol. 2007 Mar 9;3(3):e37
references: 17352530
references: Genome Res. 2009 Feb;19(2):266-75
references: 18997002