Nucleoplasmic proteins constitute a large component of the inner nucleus, but their role in chromatin remodeling during transcription and differentiation processes is poorly understood. The association of chromatin with the nuclear periphery is cell type-specific, and has been implicated in gene regulation by dynamically modulating gene accessibility during normal development 11, 16. In addition, abundant nucleoplasmic proteins serve as structural scaffolds spanning the nucleus, and specific inner nuclear proteins have been implicated in maintenance of eu- and heterochromatin architecture 14, 15.Ĭoordinated regulation of spatial and temporal chromatin repositioning is important for proper gene expression during development and differentiation.
Nuclear speckles, for example, act as functional centers that organize active gene loci to form euchromatic districts 12, 13.
Conversely, detachment from the nuclear periphery frequently correlates with gene activation, reflecting counterforces generated by intra-nuclear substructures. At the nuclear periphery, a meshwork of lamina proteins provides anchoring sites for genomic loci, and attachment is often accompanied by gene inactivation 11. Two well-characterized proteins, CCCTC-binding factor (CTCF) and cohesin, organize topological chromatin domains and mediate chromatin interactions of individual genomic loci 9, 10. Global reorganization of chromatin interactions and compartmentalization occurring during differentiation 8 requires proper chromosome positioning, but the involvement of nuclear components in this process is unknown.Īrchitectural proteins play a critical role in chromatin organization and function. In active regions of the genome, transcription factors and co-activators form condensates that compartmentalize the transcription machinery and drive gene activation 5, 6, 7. For example, droplets of heterochromatin protein 1 (HP1) facilitate sequestration of compacted chromatin, which may result in steric exclusion of regulatory proteins, such as RNA polymerase, from the underlying DNA 3, 4. Recent biophysical studies suggest that distinct chromatin regions may be pulled together or move away from each other by phase-separated nuclear condensates. The A and B compartments correspond to the structures and characteristics of known euchromatin and heterochromatin, respectively 1, 2. Recent advances in genome-wide analysis of chromosome conformation have provided molecular information regarding chromosome folding, and partitioned the genome into two compartments. The nucleus is spatially organized by chromosome and interchromatin functional components. Our findings indicate Matr3 negatively affects cell fate transitions and demonstrate that a critical inner nuclear protein impacts occupancy of architectural factors, culminating in broad effects on chromatin organization and cell differentiation. This association is conserved in embryonic stem cells. Destabilization of CTCF and cohesin binding correlates with altered transcription and accelerated differentiation. Matr3 protein interacts with CTCF and the cohesin complex, and its loss perturbs their occupancy at a subset of sites. Here we demonstrate that loss of the nuclear scaffolding protein Matrin-3 (Matr3) in erythroid cells leads to morphological and gene expression changes characteristic of accelerated maturation, as well as broad alterations in chromatin organization similar to those accompanying differentiation.
Despite an established contribution of nuclear membrane proteins to developmental gene regulation, little is known regarding the role of inner nuclear proteins. Precise control of gene expression during differentiation relies on the interplay of chromatin and nuclear structure.