揭示4D基因组学奥秘：空间折叠与远程调控解析

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4D基因组学是一个前沿的生物学领域，它将传统的基因组研究提升到一个更为立体和动态的层面，关注的是染色体的空间组织、动态变化以及它们在细胞内的三维结构与时间维度上的调控。2017年9月14日的《自然》杂志上发表的文章"The 4D Nucleome Project"由Job Dekker等人发起，该论文标志着这一领域的综述性工作开始深入探讨。在过去十年间，大规模的基因组研究项目如ENCODE（Encyclopedia of DNA Elements）、Roadmap Epigenomics、International Human Epigenome Consortium、EpiGeneSys 和 FANTOM（Functional Annotation of Transcriptional Elements in Mouse）等，已经显著地标注了成千上万的基因和数百万潜在的调控元件。这些研究揭示了基因组的基本构成，包括编码基因和非编码区域，如启动子、增强子和沉默子等，它们共同参与基因表达的调控。然而，尽管我们已经对这些元件的活性及其在特定基因上的调控有了相当的认识，但关于它们如何跨越几千甚至数百万碱基的物理距离，以及如何在空间和时间尺度上精细调控基因表达的过程，仍存在许多未知。例如，染色体的空间折叠（即所谓的3D基因组结构）对基因的表达具有显著影响，邻近的基因在空间上更有可能相互作用，这种所谓的“cis-regulation”（同源调节）是基因调控的重要组成部分。 4D基因组学的研究目标是通过整合高通量测序技术和先进的生物信息学分析，揭示基因组的动态变化模式，如染色体的动态重塑（chromatin remodeling）、核小体定位的变化以及异时性（temporal dynamics）的调控。这需要开发新的实验方法，比如单细胞RNA测序和多分辨率的染色质结构成像技术，来捕捉细胞内基因组行为的实时细节。此外，4D基因组学的应用范围也正在扩大，包括但不限于理解基因表达的时空调控在发育、疾病发生以及个体差异中的角色，以及为个性化医疗提供更深入的分子基础。未来的研究还将探索如何利用这些发现来优化基因疗法的设计，以及预测和干预复杂的生理和病理过程。总结来说，4D基因组学是一个充满挑战和机遇的领域，它不仅扩展了我们对基因组结构和功能的理解，而且有望推动生物医学研究的革新，促进精准医疗的发展。

14 SEPTEMBER 2017 | VOL 549 | NATURE | 219

PERSPECTIVES

doi:10.1038/nature23884

The 4D nucleome project

Job Dekker

, Andrew S. Belmont

, Mitchell Guttman

, Victor O. Leshyk

, John T. Lis

, Stavros Lomvardas

, Leonid A. Mirny

Clodagh C. O’Shea

, Peter J. Park

, Bing Ren

, Joan C. Ritland Politz

, Jay Shendure

, Sheng Zhong

& the 4D Nucleome

Network*

he human genome contains over 20,000 genes and a larger number

of regulatory elements. Large-scale studies over the last decade

have catalogued these components of our genome and the cell

types in which they are active. The ENCODE, Roadmap Epigenome,

International Human Epigenome Consortium, EpiGeneSys (http://www.

epigenesys.eu/en/) and FANTOM projects

1–4

have annotated thousands

of genes and millions of candidate regulatory elements. However, our

understanding of the mechanisms by which these elements exert regula-

tory effects on specific target genes across distances of kilobases, and in

some cases megabases, remains incomplete.

The spatial folding of chromosomes and their organization in the

nucleus have profound effects on gene expression. For example, spatial

proximity is necessary for enhancers to modulate transcription of target

genes (for example, refs 5–7), and clustering of chromatin near the nuclear

lamina is correlated with gene silencing and replication timing

8,9

. In

addition, genome-wide association studies have identified large numbers

of disease-associated loci, and the majority of these loci are located in

distal, potentially regulatory, noncoding regions (for example, ref. 10).

In cancer cells, genomic rearrangements frequently occur and these

are at least in part guided by the three-dimensional organization of the

nucleus

11,12

. These data emphasize the importance of distal elements

for gene regulation and suggest an exciting opportunity to uncover the

fundamental mechanisms of disease through the mapping of long-range

chromatin interactions and three-dimensional genome organization.

Therefore, to determine how the genome operates, we need to understand

not only the linear encoding of information along chromosomes, but also

its three-dimensional organization and its dynamics across time, that is,

the ‘4D nucleome’. Concomitantly, we must pursue deeper knowledge

of the biophysical and molecular factors that determine genome

organization, and how this organization contributes to gene regulation

and other nuclear activities. Here we outline the goals and strategies of the

4D Nucleome (4DN) Network. This Network builds on other consortia

and efforts focusing on (epi-)genome analysis outlined above and adds

spatial and temporal dimensions to explore how the genome is organized

inside cells and how this relates to genome function.

The nucleus is not a homogeneous organelle, but consists of distinct

nuclear structures and non-chromatin bodies as well as defined chromo-

somal regions, such as centromeres, telomeres and insulator bodies, that

have been shown to cluster with each other and other genomic regions to

define distinct nuclear compartments

13,14

. Examples of nuclear structures

include the nuclear lamina and nuclear pores. Examples of nuclear com-

partments include the heterochromatic compartment, while examples of

nuclear bodies include nucleoli, nuclear speckles, paraspeckles, and Cajal

and PML (promyelocytic leukaemia) bodies. Chromosome conformation

capture (3C) approaches

15,16

have yielded additional insights by char-

acterizing genome-wide chromatin folding at kilobase resolution

6,17,18

These studies have shown that the genome is compartmentalized in active

and inactive spatial compartments at the scale of the nucleus, and that

within each compartment, folding of chromatin fibres brings together loci

and regulatory elements that are otherwise separated by large genomic

distances. CTCF, the cohesin complex and other DNA-binding proteins,

as well as RNAs, have roles in organizing chromatin domains and long-

range interactions between DNA loci

18–24

. These studies indicate that the

genome is intricately organized within the nucleus and that this organi-

zation has a critical role in gene regulation and activity.

During the past decade marked innovation in chromosome and

nuclear structure analysis has occurred. Genomic approaches for

mapping chromatin interactions, such as 3C, 4C (circular 3C, or 3C-on-

chip), 5C (3C-carbon copy), Hi-C, and chromatin-interaction analysis

by paired-end-tag sequencing (ChIA-PET)

, are yielding genome-wide

chromatin interaction maps at unprecedented resolution. Live-cell and

super-resolution microscopic approaches, combined with application of

new ways (for example, CRISPR–Cas9-based systems) to visualize loci

and sub-nuclear structures are beginning to provide detailed views of the

organization and dynamics of chromatin inside (living) cells

25–31

. There

has also been pronounced progress in analysing chromosome structural

data, producing structural models for chromosome folding

32,33

. However,

despite this progress, a comprehensive understanding of the 4D nucleome

is still lacking. This is partly due to the fact that different experimental cell

systems and approaches are used that together with the absence of shared

The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and

mouse genomes in space and time with the goal of gaining deeper mechanistic insights into how the nucleus is organized

and functions. The project will develop and benchmark experimental and computational approaches for measuring

genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other

genome functions. Validated experimental technologies will be combined with biophysical approaches to generate

quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells.

Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Howard Hughes Medical Institute, Worcester, Massachusetts

01605, USA.

Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Illinois 61801, USA.

Division of Biology and Biological Engineering, California Institute of

Technology, Pasadena, California 91125, USA.

Department of Bioengineering, University of California San Diego, La Jolla, California 92093, USA.

Department of Molecular Biology and Genetics,

Cornell University, Ithaca, New York 14853, USA.

Department of Biochemistry and Molecular Biophysics, Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University,

New York, New York 10027, USA.

Institute for Medical Engineering and Science, and Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,

USA.

Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.

Department of Biomedical Informatics, Harvard Medical School, Boston,

Massachusetts 02115, USA.

Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, University of California

San Diego, La Jolla California 92093, USA.

Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.

Department of Genome

Sciences, University of Washington, Howard Hughes Medical Institute, Seattle, Washington 98109, USA.

*A list of participants and their affiliations appears in the Supplementary Information.

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