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The role of mediator complex subunit 12 (MED12) in the murine reproductive tract

Mittal, Priya (2016) The role of mediator complex subunit 12 (MED12) in the murine reproductive tract. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Uterine leiomyomas are benign neoplasms arising from smooth muscle cells of the uterus. They are clinically diagnosed in 25% of women and are associated with significant morbidity. Whole exome approaches have identified heterozygous somatic mutations in the mediator complex subunit 12 (MED12) in about 70% of leiomyomas with a majority harboring in exon 2 of MED12 with c.131G>A being the most common SNV. MED12 protein is part of the large mediator complex and is involved in transcriptional regulation of RNA Polymerase II. To elucidate the role of MED12 exon 2 variants in leiomyomagenesis, we generated three different mouse models of Med12; loss-of-function, dominant-negative and gain-of-function mouse models.
The loss-of-function females lacked any leiomyoma-like lesions, instead the reproductive tracts were hypoplastic and the females were infertile.
We engineered a model where we conditionally floxed Med12 c.131G>A cDNA and inserted into the ROSA26 locus to generate Med12 ROSA knock-in mice. Amhr2-cre was used to drive the expression of the mutant Med12 from the ROSA locus either in the absence (gain-of-function) or presence (dominant-negative) of X-chromosome wild-type Med12 in the uterine mesenchyme. Uteri from (gain-of-function) females displayed leiomyoma-like lesions in about 87% of females. Similar characterization of uteri of dominant negative females revealed the development of leiomyoma-like lesions, but with appearance of smaller lesions and lower penetrance (50% of females) as compared to the gain-of-function model, leading us to conclude that the Med12 exon 2 variants are likely to cause uterine leiomyomas via gain-of-function mechanism.
Array comparative genomic hybridization (aCGH) of mouse tumors displayed genome wide aberrations, affecting general tumor pathways. Interestingly, several regions previously implicated in human leiomyomas were also shared by the mouse leiomyomas, revealing the similarities between human and mouse leiomyomas. This data suggests that Med12 exon 2 mutations are precursors to genomic rearrangements leading to an unstable genome. The public health significance of this work includes the successful development of the first animal model for uterine leiomyomas, which will be an invaluable tool to understand the role of MED12 in leiomyoma genesis, as well as provide a unique platform to test targeted therapeutics as an alternative to hysterectomies.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Mittal, Priyaprp18@pitt.eduPRP180000-0002-6270-3460
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRajkovic, Aleksandarrajkovic@upmc.eduALR110
Committee MemberSurti, Urvashisurti@pitt.eduSURTI
Committee Memberurban, Zsolturbanz@pitt.eduURBANZ
Committee MemberBarmada, M. Michaelbarmada@pitt.eduBARMADA
Committee MemberPadiath, Quasarqpadiath@pitt.eduQPADIATH
Date: 27 January 2016
Date Type: Publication
Defense Date: 23 October 2015
Approval Date: 27 January 2016
Submission Date: 23 November 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 133
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: MED12; Mouse; Uterine Leiomyomas;Genetics;Fibroids
Date Deposited: 27 Jan 2016 22:04
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/26439

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