# Chap6 4DN Project ## [4D nucleome project](doi:10.1038/nature23884) 1. What is 4D Nucleome
2. Current dilemma in understanding 4D nucleome
3. Goals and Strategies
4. Structure of the 4DN Network
5. Data sharing and standards
### What is 4D Nucleome 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’. ### Current dilemma in understanding 4D nucleome * Different experimental cell systems and approaches are used that together with the absence of **shared benchmarks** for assay performance have led to observations that cannot be directly compared. * Iimited ability to **integrate** different data types (for example, chromatin interaction data and imaging-based distance measurements)。 * Lack of approaches that can measure and account for **cell-to-cell variability** in chromosome and nuclear organization. * Lack of **mechanistic insights** into the relationships between chromosome conformation and nuclear processes, including transcription, DNA replication and chromosome segregation. ### Goals and Strategies #### Goals: * Develop, benchmark, validate and standardize a wide array of **technologies to analyse** the 4D nucleome * **Integrate**, analyse and model datasets obtained with these technologies to obtain a comprehensive view of the 4D nucleome * Investigate the **functional role** of various structural features of chromosome organization in transcription, DNA replication and other nuclear processes. #### Strategies: * A set of **common cell lines** will be studied to enable direct cross- validation of data that are obtained with different methods [table](https://www.nature.com/articles/nature23884#t1). * **Standards for data formats** and quality will be established so that data can be shared broadly. * **Computational and analytical tools** will be developed to analyse individual datasets and to integrate, compare and cross-validate data obtained with different technologies. * Develope multiple ways to measure **how DNA and trans-acting factors influence** on the 4D nucleosome. * Develop a **consistent terminology** to describe nuclear features and biophysically derived principles guiding chromosome folding. * **Compare and integrate** the wealth of information that is anticipated to be generated by the Network. * Build a shared **database** and a public 4DN data browser includes all data, detailed protocols, engineered cell lines and reagents used across the Network. ### [Structure of the 4DN Network](https://commonfund.nih.gov/4Dnucleome) | Consortium | Institution Name | Objections | | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ---------------------------------------------------------------------------------------------------------------------------------------------------------------- | |

NOFIC
(Nuclear Organization
and Function
Interdisciplinary
Consortium)

| UNIVERSITY OF SOUTHERN CALIFORNIAUNIV OF ILLINOIS URBANA-CHAMPAIGNUNIV OF MASSACHUSETTS MED SCH WORCESTERLUDWIG INSTITUTE FOR CANCER RESEARCH LTDJACKSON LABORATORYUNIV OF WASHINGTON | benchmark toolsFind best approachIntegrate approachesDraft model of 4DN | | **Imaging Tools** | YALE UNIVERSITYCALIFORNIA INSTITUTE OF TECHNOLOGYPRINCETON UNIVERSITYEUROPEAN MOLECULAR BIOLOGY LABORATORYUNIV OF MASSACHUSETTS MED SCH WORCESTERUNIVERSITY OF CALIFORNIA AT DAVISSTANFORD UNIVERSITYSALK INSTITUTE FOR BIOLOGICAL STUDIESALBERT EINSTEIN COLLEGE OF MEDICINE | High res methodHigh-throughputdynamic imagingLive cell | |

DCIC
(Network Data
Coordination
and Integration
Center)

| HARVARD MEDICAL SCHOOLWASHINGTON UNIVERSITY | collect, store, curate, display and analyze datadevelope efficient submission pipelineshigh-quality, well- annotated, public accessibleuser-friendly data portal | |

Network
Organizational
Hub

| UNIVERSITY OF CALIFORNIA SAN DIEGO | web portal for 4DNintegrated, bersatile data managementretrieval, analysis and vis systemtrain and update 4DN members and collaboraters | | **Nuclear Bodies and Compartments** | PRINCETON UNIVERSITYSCRIPPS RESEARCH INSTITUTEPRINCETON UNIVERSITYFRED HUTCHINSON CANCER RES CENTERCALIFORNIA INSTITUTE OF TECHNOLOGYUNIV OF MASSACHUSETTS MED SCH WORCESTERCOLUMBIA UNIVERSITY HEALTH SCIENCES | deciphering function of compartmentsnucleoplasmic phase transitionsreversibly disrupt nuclear bodies | | **Nucleomics Tools** | THE BABRAHAM INSTITUTECALIFORNIA INSTITUTE OF TECHNOLOGYBAYLOR COLLEGE OF MEDICINECORNELL UNIVERSITYUNIVERSITY OF PENNSYLVANIA | pipeline for single-cell hi-cmap dynamic organizationsplit pool barcodingdistance-Hi-Csuper resolution vis | ### Data sharing and standards * Need to develope common formats to represent three-dimensional interactions. * Efficient data structure to store sparse matrix (interaction matrix is sparse) * Standards to unify data and metadata from different manufacturers for imaging technologies. * Define a set of appropriate metadata fields and minimum metadata requirements such that sufficient and useful details are available to other investigators outside the Network. * Develope a set of measures for assessing data quality and determining appropriate thresholds. ## Reference \[1] Dekker, Job, et al. "The 4D nucleome project." Nature 549.7671 (2017): 219.\ \[2]