2026-09-19T06:13:02Zhttps://dspace.mit.edu/server/oai/requestoai:dspace.mit.edu:1721.1/1276972026-06-16T18:51:47Zcom_1721.1_7582com_1721.1_7581col_1721.1_131022
Richard A. Young.
Manteiga, John C.
Massachusetts Institute of Technology. Department of Biology.
Massachusetts Institute of Technology. Department of Biology
2020-09-25T20:02:54Z
2020-09-25T20:02:54Z
2020
2020
https://hdl.handle.net/1721.1/127697
1196085936
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2020
Cataloged from student-submitted PDF of thesis.
Includes bibliographical references.
Gene regulation underlies the control of cell identity, development, and disease. Transcription of genes is regulated by DNA elements called enhancers, which are bound by transcription factors and coactivators, leading to the recruitment of RNA polymerase II and the production of RNA. Enhancers are thought to loop to specific gene promoters to stimulate transcription, but the mechanisms that cause enhancers to selectively loop to specific gene promoters is not well understood. In this thesis, I first describe new insights into enhancer-promoter loop specificity from studies examining the mechanisms that allow tumor-specific super-enhancers to loop to the MYC oncogene in diverse cancer types (Schuijers and Manteiga et al., 2018). While conducting these studies, it was proposed that super-enhancers and the factors associated with them form liquid-liquid phase-separated condensates.
Following this proposal, I contributed to collaborative studies that strongly supported this model (Boija et al., 2018; Sabari et al., 2018, see Appendix I and II of this thesis). This model of transcription led me to ask how key transcriptional components could be recruited into super-enhancer condensates. I performed studies showing that the interaction of RNA polymerase II with these condensates involves the large heptapeptide repeat of the C-terminal domain (CTD) of the enzyme. Furthermore, these studies provided evidence that phosphorylation of the CTD, which is associated with the initiation to elongation transition, weakens these interactions, thus facilitating the transition of RNA polymerase II into different condensates involved in co-transcriptional splicing of the nascent transcript (Guo and Manteiga et al., 2019).
These studies provide new insights into the mechanisms of enhancer-promoter interaction, roles for the RNA polymerase II CTD in the enzyme's partitioning into nuclear condensates, and a role for phosphorylation in switching the nuclear condensate partitioning behavior of RNA polymerase II.
by John C. Manteiga.
Ph.D.
Ph.D. Massachusetts Institute of Technology, Department of Biology
148 pages
eng
Massachusetts Institute of Technology
MIT theses may be protected by copyright. Please reuse MIT thesis content according to the MIT Libraries Permissions Policy, which is available through the URL provided.
http://dspace.mit.edu/handle/1721.1/7582
Biology.
Enhancers and phase separation in the control of gene expression
Thesis
application/pdf
2020-09-25T20:02:54Z
Publication
Doctoral
Bio
unknown
unknown
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<Abstract>Gene regulation underlies the control of cell identity, development, and disease. Transcription of genes is regulated by DNA elements called enhancers, which are bound by transcription factors and coactivators, leading to the recruitment of RNA polymerase II and the production of RNA. Enhancers are thought to loop to specific gene promoters to stimulate transcription, but the mechanisms that cause enhancers to selectively loop to specific gene promoters is not well understood. In this thesis, I first describe new insights into enhancer-promoter loop specificity from studies examining the mechanisms that allow tumor-specific super-enhancers to loop to the MYC oncogene in diverse cancer types (Schuijers and Manteiga et al., 2018). While conducting these studies, it was proposed that super-enhancers and the factors associated with them form liquid-liquid phase-separated condensates.</Abstract>
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