The Rivera-Mulia Lab - RT and 3D genome organization

In the last decade, great progress in our understanding of the spatial organization of the genome was achieved with the explosion of chromosome conformation capture technologies (from 3C to Hi-C).

Chromosomes are partitioned into units that occupy distinct compartments according to the temporal order of replication (replication timing – RT). On a large scale, chromosomes are separated into active (“A”) or inactive (“B”) compartments defined by principal component analysis of Hi-C data. At the sub-megabase scale, chromosomes are folded into self-interacting topologically associating domains (TADs).

3D genome organization modulates distinct nuclear processes and is coordinated with RT and nuclear lamina association. In fact, A/B compartments align with early and late replication, respectively and TADs align with the replication domains. Late RDs are also associated with the nuclear periphery and correspond to the lamin-associated domains (LADs).

RT and A/B compartmentalization are highly conserved and alterations in RT and 3D organization are associated with many diseases, underscoring the importance of genome architecture in gene function regulation.

RT and genome organization of a chromosomal region in human fibroblasts. A) RT domains align with Hi-C compartments and LaminB1 contact maps (DamID). B) Replication domain model. Rivera-Mulia and Gilbert, 2016.

Genome-wide analysis of nuclear architecture and function

Genomic technologies based on next-generation sequencing (NGS) allow the characterization of nuclear organization and function.

In the Rivera-Mulia lab, we perform genome-wide analyses of the temporal order of DNA replication (Repli-seq), 3D genome architecture (Hi-C), gene expression (RNA-seq) and chromatin accessibility to identify regulatory mechanisms of nuclear organization.

Analysis of RT, 3D genome organization, enhancer-promoter interactions, gene expression and chromatin accessibility. Top: Methods for genome-wide analysis of RT, Hi-C and promoter capture Hi-C (PC-Hi-C), nuclear RNA-seq and chromatin accessibility measured by Assay for Transposase Accessible Chromatin (ATAC-seq). Bottom: Representative genomic region on chromosome 1 showing changes in RT linked to differences in Hi-C matrices, compartments A and B, gene expression, chromatin accessibility, and enhancer-promoter interactions. Rivera-Mulia, et al., 2018.