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
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.
A set of common cell lines will be studied to enable direct cross- validation of data that are obtained with different methods table.
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.
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
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
HARVARD MEDICAL SCHOOLWASHINGTON UNIVERSITY
collect, store, curate, display and analyze datadevelope efficient submission pipelineshigh-quality, well- annotated, public accessibleuser-friendly data portal
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
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