UNIVERSITY OF CALIFORNIA, SAN DIEGO
Dissecting Enhancer Functions in Signal Induced Transcription Programs
A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy
in
Biology
by
Yiren Hu
Committee in charge:
Professor Michael Geoff Rosenfeld, Chair Professor Christopher K. Glass Professor Cornelis Murre Professor Amy Pasquinelli Professor Samuel Pfaff
2018
The Dissertation of Yiren Hu is approved, and it is acceptable in quality and form for publication on microfilm and electronically:
Chair
University of California, San Diego 2018
iii Table of Contents
Signature Page ...... iii
Table of Contents ...... iv
Acknowledgements ...... viii
Vita ...... x
Publications ...... x
Abstract of the Dissertation ...... xi
Introduction ...... 1
Chapter 1: Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation ...... 4
Chapter 2: JMJD6 Licenses Estrogen Receptor α-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/ MED12 Co-activator Complex ...... 26
Chapter 3: KDM2B and ERα Function as Dual Transcription Brakes to Curb Inflammation ...... 59
Chapter 4: Discussion ...... 73
Appendix:Figures ...... 78
References ...... 134
iv List of Figures
Figure 1: Estrogen-Induced Loading of Condensins to ER-α-Bound Active Enhancers, Continued ...... 78
Figure 2: ER-α Interacts with Condensins ...... 80
Figure 3: Condensin I and Condensin II Control ER-α-Regulated Gene Activation in a Partially Overlapping Manner ...... 81
Figure 4: Condensins Are Needed for Full eRNA Activation and Enhancer:Promoter Looping, Continued ...... 82
Figure 5: Condensins License Appropriate Coactivator and Corepressor Recruitment during Enhancer Activation ...... 84
Figure 6: Condensin-Dependent Recruitment of HECTD1 Is Required for E2-Induced eRNA Activation, Continued ...... 85
Figure 7: Evidence Suggesting RIP140 as a Polyubiquitination Substrate of HECTD1, Continued ...... 87
Figure 8: JMJD6 Binding was Induced by Estrogen on ERα-Bound Active Enhancers, Continued...... 101
Figure 9: JMJD6 is Required for Transcriptional Activation of ERα-Bound Active Enhancers, Continued...... 103
Figure 10: JMJD6 Regulates Estrogen-induced Coding Gene Transcription, Continued.105
Figure 11: JMJD6 Regulates MED12 Function in Estrogen-Induced Transcriptional Activation, Continued...... 107
Figure 12: JMJD6 Regulates MED12 Interaction with CARM1 and hence MED12 Methylation and Chromatin Binding, Continued...... 109
Figure 13:JMJD6 is Required for Estrogen-Induced Breast Cancer Cell Growth and Tumorigenesis, Continued...... 111
Figure 14: A Proposed Model of JMJD6 Function in Estrogen/ERα-Regulated Enhancer and Coding Gene Activation...... 113
Figure 15: E2 Downregulates TNFα Transcription Program ...... 122
Figure 16: ERα is Tethered to NFκB Enhancers to Repress Transcription ...... 123
v Figure 17: KDM2B represses inflammation at basal condition ...... 124
Figure 18: KDM2B Nucleates PRC1 to Repress Inflammation ...... 125
Figure 19: KDM2B Represses Inflammation in Macrophage ...... 126
Figure 20: GRIP1 mediates ERα repressive effects on NFκB genes ...... 127
Figure S1: Additional descriptive data of condensins localization in the genome ...... 89
Figure S2: Additional descriptions of condensins ChIP-Seqs and their localization to active enhancers...... 90
Figure S3: Localization of condensins in mitotic MCF-7 cells, condensin/ER-α interaction and condensin I / II relationship, Continued...... 91
Figure S4: Efficient knockdown of condensins and its effects on estroge