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Transcriptional Regulation Of MicroRNA Genes And The Regulatory Networks In Which They Participate

Corcoran, David Lee (2008) Transcriptional Regulation Of MicroRNA Genes And The Regulatory Networks In Which They Participate. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Corcoran, David Leedavid.corcoran@duke.edu
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberFeingold, Eleanorfeingold@pitt.eduFEINGOLD
Committee MemberBarmada, M. Michaelbarmada@pitt.eduBARMADA
Committee MemberKaminski, Naftalikaminx@upmc.edu
Committee MemberBenos, Panayoitis Vbenos@pitt.eduBENOS
Date: 28 September 2008
Date Type: Completion
Defense Date: 8 July 2008
Approval Date: 28 September 2008
Submission Date: 1 August 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: microRNA network; microRNA promoter; microRNA transcription; let-7d; microRNA regulation; transcription factor binding
Other ID: http://etd.library.pitt.edu/ETD/available/etd-08012008-150441/, etd-08012008-150441
Date Deposited: 10 Nov 2011 19:56
Last Modified: 15 Nov 2016 13:47
URI: http://d-scholarship.pitt.edu/id/eprint/8802

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