Abstract/Details

Transcriptional regulation of microRNA genes and the regulatory networks in which they participate


2008 2008

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Abstract (summary)

MicroRNA genes are short, non-coding RNAs that function as post-transcriptional gene regulators. Although they have been implicated in organismal development as well as a variety of human diseases, there is still surprisingly little known about their transcriptional regulation. The understanding of microRNA transcription is very important for determining their regulators as well as the specific role they may play in signaling cascades. This dissertation focused on the comparison of mammalian microRNA promoters and upstream sequences to those of known protein coding genes. This dissertation is also focused on determining potential regulatory networks that microRNA genes may participate in, particularly those networks involved in the TGFβ/SMAD signaling pathway.

The comparison of intergenic microRNA upstream sequences to those of protein coding genes revealed that the former are up to twice as conserved as the latter, except in the first 500 base pairs where the conservation is similar. Further investigation of the upstream sequences by RNA Polymerase II ChIP-chip revealed the transcription start site for 35 primary-microRNA transcripts. The identification of features capable of distinguishing core promoter regions from background sequences using a support vector machine approach revealed that the transcription start site of primary-microRNA genes share the same sequence features as protein coding genes. These results suggest that in fact microRNA genes are transcribed by the same mechanism by which protein coding genes are transcribed. This information allowed us to then identify the regulatory elements of microRNA genes in the same manner in which we use for protein coding genes. Identification of a SMAD family transcription factor binding site upstream of the human let-7d microRNA revealed a feed-forward regulatory circuit involved in epithelial mesenchymal transition. This provided the first evidence of a direct link between a growth factor and the expression of a microRNA gene.

The understanding of microRNA transcriptional regulation has great public health significance. The ability to understand how these post-transcriptional gene regulators function in cellular networks may provide new molecular targets for cures or therapies to a variety of human diseases.

Indexing (details)


Subject
Genetics
Classification
0369: Genetics
Identifier / keyword
Biological sciences; MicroRNA network; MicroRNA promoter; MicroRNA regulation; MicroRNA transcription; Transcription factor binding
Title
Transcriptional regulation of microRNA genes and the regulatory networks in which they participate
Author
Corcoran, David Lee
Number of pages
107
Publication year
2008
Degree date
2008
School code
0178
Source
DAI-B 69/11, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549894544
University/institution
University of Pittsburgh
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3335742
ProQuest document ID
304496836
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304496836
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