Fundamental Principles of 3D Genomic Organization Public
Nichols, Michael (Fall 2020)
Published
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
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