Fundamental Principles of 3D Genomic Organization Open Access

Abstract

The three-dimensional (3D) conformation of chromatin in the nucleus is an elusive but essential aspect of genomic regulation. Only with recent advances in techniques such as Hi-C has it been possible to assess this structure at the sequence level across the entire genome. A variety of architectural patterns are observed in these conformational assays. Here we present insights into the fundamental principles that give rise to these structural phenomena. Two independent processes can explain the majority of the conformational features of the genome. Extrusion of DNA loops by Structural Maintenance of Chromosomes (SMC) complexes form stable CTCF loops and associated topological domains. We present the theoretical logic of this model and a mechanistic explanation for how SMC complexes may extrude loops. Separately, chromatin segments associate preferentially with other regions with similar chromatin features. We show this agglomeration directly corresponds to various epigenetic features and extends beyond canonical binary segregation of transcriptionally active and inactive chromatin. Together these processes organize the genome, playing essential roles in transcriptional regulation and likely other aspects of genome function.

Table of Contents

Table of Contents

Chapter 1: Introduction. 1

The chromosome as a folded polymer 1

Features of genomic architecture. 3

Figures. 11

References. 12

Chapter 2: A CTCF code for 3D genome architecture. 16

Summary. 16

Main Text 16

Figures. 20

References. 21

Chapter 3: A tethered inchworm model of SMC DNA translocation. 23

Abstract 23

Main Text 23

Figures. 34

References. 36

Chapter 4: Evolutionarily conserved principles predict 3D chromatin organization. 43

Summary. 43

Introduction. 44

Results. 46

Discussion. 63

References. 66

Figures. 74

Methods. 113

Chapter 5: Dynamic compartmentalization formed by conserved forces. 126

Abstract 126

Introduction. 127

Results. 131

Discussion. 144

Figures. 147

Methods. 161

References. 166

Chapter 6: Discussion. 169

Conclusions. 169

Future directions. 170

References. 173

Tables

Table 4.S1. HiChIP and ChIA-PET mapping statistics performed in Kc167 cells to the dm6 genome for H3K27ac.

Table 4.S2. HiChIP and ChIA-PET mapping statistics performed in Kc167 cells to the dm6 genome for H3K27me3.

Table 4.S3. HiChIP and ChIA-PET mapping statistics performed in Kc167 cells to the dm6 genome for RNAPIISer2ph, CP190, and RNAPII.

Figures

Figure 1.1. Compartments and CTCF loops organize the genome

Figure 2.1. Model of orientation biased CTCF looping

Figure 3.1. The loop extrusion model

Figure 3.2. The tethered inchworm model

Figure 4.1. Drosophila has Fine-Scale Compartments

Figure 4.2. Compartments Explain Domain Organization in Drosophila

Figure 4.3. RNAPII Depletion Alters Drosophila Chromatin Organization

Figure 4.4. Architectural Proteins Insulate Gene-to-Gene Interactions

Figure 4.5. Transcriptional States Explain 3D Chromatin Interactions throughout Eukarya

Figure 4.6. Compartments are Fine-scale Structures in Human Cells

Figure 4.7. Transcriptional States and CTCF Loops Contribute to Formation of Domains in Human Cells

Figure 4.S1. Supplement to Drosophila has Fine-Scale Compartments

Figure 4.S2. Supplement to Compartments Explain Domain Organization in Drosophila

Figure 4.S3. Supplement to RNAPII Depletion Alters Drosophila Chromatin Organization

Figure 4.S4. Supplement to Architectural Proteins Insulate Gene-to-Gene Interactions

Figure 4.S5. Supplement to Transcriptional States Explain 3D Chromatin Interactions throughout Eukarya

Figure 4.S6. Supplement to Compartments are Fine-scale Structures in Human Cells

Figure 4.S7. Supplement to Transcriptional States and CTCF Loops Contribute to Formation of Domains in Human Cells

Figure 5.1. Divergent compartmentalization between GM12878 and HCT-116

Figure 5.2. Chromosome sortings of HCT-116 chromosome 14

Figure 5.3. Histone modifications can predict compartmentalization using learned attraction-repulsion relationships

Figure 5.4. Attraction-repulsion relationships are consistent across cell types

Figure 5.5. Attraction-repulsion relationships explain compartmentalization in Drosophila

Figure 5.S1. Supplement to divergent compartmentalization between GM12878 and HCT-116

Figure 5.S2. Supplement to chromosome sortings of HCT-116 chromosome 14

Figure 5.S3. Supplement to histone modifications can predict compartmentalization using learned attraction-repulsion relationships

Figure 5.S4. Supplement to attraction-repulsion relationships are consistent across cell types

Figure 5.S5. Supplement to attraction-repulsion relationships explain compartmentalization in Drosophila

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Bioinformatics Biology, Genetics Biology, Molecular
Keyword	CTCF Loop extrusion Chromatin Cohesin
Committee Chair / Thesis Advisor	Victor Corces, Emory University
Committee Members	Roger Deal, Emory University Jeremy Boss, Emory University William Kelly, Emory University David Katz, Emory University

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