UNIVERSITY OF CALIFORNIA, SAN DIEGO

Dissecting Enhancer Functions in Signal Induced 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 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 ...... 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