Gene regulation in the 3D genome.

The spatial organization of the genome is essential for the precise control of gene expression. Recent advances in sequencing and imaging technologies allow us to explore the 3D genome and its relationship to gene regulation at an unprecedented scale. In this review, we provide an overview of lessons learned from studying the chromatin structure and their implications in communications between gene promoters and distal cis-regulatory elements, such as enhancers. We first review the current knowledge of general genome organization, followed by the importance of chromatin folding in gene regulation. Next, we proceed to a brief survey of the recently developed chromosome conformation capture technologies, as well as most widely adopted read-outs from such data. We then introduce two emerging models that offer explanations regarding how distal enhancers achieve transcriptional control of target genes in the 3D genome. Last, we discuss the promising prospects of leveraging knowledge in chromatin spatial organization for studying complex diseases and traits. General Features of Genome Structure To fit the entire genome of 2-m-long human DNA sequences, containing 3 billion nucleotides, in the nucleus of a diameter of 10 mm, DNA has to be packed and organized achieving 10 compaction. In vitro structure study of the chromatin showed that every 146 bp of DNA is wrapped around nucleosome (11 nm diameter), providing 5–6 compaction. At the next level, nucleosomes are compacted into the 30 nm chromatin fiber, achieving an additional 50 compaction (1). The chromatin is thought to be further compacted into fibers sized several nanometers. However, this hierarchical model of chromosome compaction was challenged by new findings of chromatin structure in nucleus using ChromEMT (2). Unlike in vitro, chromatin is a disorganized chain with diameter 5–24 nm in situ. Chromatin chains are flexible and compacted in different densities with various particle arrangements and conformations (2). Such observation suggests that chromatin fibers are organized at different local chromatin concentrations instead of being folded in a hierarchical order. It remains elusive how precisely such observed chromatin polymer structure determines DNA accessibilities and gene regulation. We learned chromosomes are organized in chromosome territories as the basic structure of genome organization by cell biology studies (3) (Fig. 1A). Chromosome territories are arranged in a somewhat nonrandom fashion so that small, gene-rich chromosomes tend to locate at the center of the nucleus (4). More recently, molecular approaches with chromatin conformation assays have revealed many insights regarding chromatin structure at different resolutions. For example, the first survey of genome-wide chromatin interaction, at 1 Mb resolution, showed that the genome is partitioned into compartments ‘A’ and ‘B’. ‘A’ is the open and actively transcribed regions and ‘B’ the compacted and repressed regions of the genome (5) (Fig. 1B). Later, several studies were conducted in an attempt to gain a better understanding of spatial organization of genomes by increasing data resolution with in-depth sequencing (6,7). Collective results from these Received: April 30, 2018. Revised: April 30, 2018. Accepted: April 30, 2018 VC The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com R228 Human Molecular Genetics, 2018, Vol. 27, No. R2 R228–R233 doi: 10.1093/hmg/ddy164 Advance Access Publication Date: 14 May 2018