Abstract
Precise control of gene expression during differentiation relies on the interplay of chromatin and nuclear structure. Despite an established contribution of nuclear membrane proteins to developmental gene regulation, little is known regarding the role of inner nuclear proteins. 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. Matr3 protein interacts with CTCF and the cohesin complex, and its loss perturbs their occupancy at a subset of sites. Destabilization of CTCF and cohesin binding correlates with altered transcription and accelerated differentiation. This association is conserved in embryonic stem cells. 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.
Highlights
Precise control of gene expression during differentiation relies on the interplay of chromatin and nuclear structure
Similar to mouse erythroleukemia (MEL) cells, Matr[3] KO embryonic stem (ES) cells proliferated at the same rate as parental cells, and changes in gene expression were more evident upon differentiation (Fig. S6c–e)
Nuclear architecture contributes to chromosome compartmentalization and organization and influences cell differentiation
Summary
Precise control of gene expression during differentiation relies on the interplay of chromatin and nuclear structure. 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. Destabilization of CTCF and cohesin binding correlates with altered transcription and accelerated differentiation This association is conserved in embryonic stem cells. Our findings indicate Matr[3] 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. Nucleoplasmic proteins constitute a large component of the inner nucleus, but their role in chromatin remodeling during transcription and differentiation processes is poorly understood. Our studies reveal unique aspects of the impact of nuclear protein-chromosomal organization on 3D genome structure and the molecular machinery underlying chromatin repositioning during development
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