Nuclear peripheral chromatin-lamin B1 interaction is required for global integrity of chromatin architecture and dynamics in human cells

Lei Chang,Shipeng Shao,Xiaoying Fan,Boxin Xue,Cheng Li,Yingping Hou,Yujie Sun,Ruifeng Li,Aibin He,Chen Li,Yiwen Zhang,Mengfan Li,Shanshan Ai

doi:10.1007/s13238-020-00794-8

Abstract

The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to detachment of lamina-associated domains (LADs) from the nuclear periphery accompanied with global chromatin redistribution and decompaction. Consequently, the inter-chromosomal as well as inter-compartment interactions are increased, but the structure of topologically associating domains (TADs) is not affected. Using live-cell genomic loci tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, chromatin compaction, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting their crucial roles in chromatin higher-order structure and chromatin dynamics.

Highlights

Chromatin in the interphase nucleus of eukaryotic cells is highly compartmentalized and structured
Given the finding that lamin B1 depletion leads to chromatin decompaction (Fig. 1), we examined whether the increased chromatin dynamics upon loss of lamin B1 was due to chromatin decompaction
We found that the relative volume of chromosomes increased significantly compared with that in control cells (Fig. 6A and 6B), but different from lamin B1 depletion which altered the position of chromosomes (Fig. 1F), Trichostatin A (TSA) treatment did not change the radial distribution of chromosome territories (Fig. 6A and 6C)

Summary

Introduction

Chromatin in the interphase nucleus of eukaryotic cells is highly compartmentalized and structured. Hierarchical chromatin architecture is composed of loops, TADs, active and inactive A/B compartments, and chromosome territories, in increasing scales. A number of architectural proteins and molecular machineries governing chromatin organization and dynamics have been identified. CTCF (Nora et al, 2017) and cohesin (Haarhuis et al, 2017; Rao et al, 2017; Schwarzer et al, 2017; Wutz et al, 2017) are partly responsible for the formation and maintenance of chromatin loops and TADs. CTCF does not impact higher-order genomic compartmentalization and cohesin even limits the segregation of A/B compartments (Nuebler et al, 2018). A few studies revealed other potential protein candidates responsible for global and hierarchical chromatin organization, including HNRNPU (Fan et al, 2018), SAFB (Huo et al, 2020) and TOPORS (Ji et al, 2020). The mechanisms that underlie the insulation and distribution of A/B compartments and chromosome territories remain poorly understood

Methods

Results

Conclusion