Microtubule-induced nuclear envelope fluctuations control chromatin dynamics in Drosophila embryos

Abstract

Nuclear shape is different in stem cells and differentiated cells and reflects important changes in the mechanics of the nuclear envelope (NE). The current framework emphasizes the key role of the nuclear lamina in nuclear mechanics and its alterations in disease. Whether active stress controls nuclear deformations and how this stress interplays with properties of the NE to control NE dynamics is unclear. We address this in the early Drosophila embryo, in which profound changes in NE shape parallel the transcriptional activation of the zygotic genome. We show that microtubule (MT) polymerization events produce the elementary forces necessary for NE dynamics. Moreover, large-scale NE deformations associated with groove formation require concentration of MT polymerization in bundles organized by Dynein. However, MT bundles cannot produce grooves when the farnesylated inner nuclear membrane protein Kugelkern (Kuk) is absent. Although it increases stiffness of the NE, Kuk also stabilizes NE deformations emerging from the collective effect of MT polymerization forces concentrated in bundles. Finally, we report that MT-induced NE deformations control the dynamics of chromatin and its organization at steady state. Thus, the NE is a dynamic organelle, fluctuations of which increase chromatin dynamics. We propose that such mechanical regulation of chromatin dynamics by MTs might be important for gene regulation.

Sizing and shaping the nucleus: mechanisms and significance

“…During Drosophila embryogenesis, the NE protein Kugelkern and dynamic microtubules were necessary to maintain normal NE morphology and chromatin dynamics and to activate zygotic gene transcription [92,93]. During differentiation of human embryonic stem cells, increased expression of lamin A/C and emerin were associated with increased nuclear size, the appearance of nuclear invaginations or lobes, and large-scale chromatin reorganization [94].…”

Mechanobiology of Chromatin and the Nuclear Interior

“…Generally, forces within the cell have been shown to cause chromatin remodeling. 45,49 Other studies have shown that direct force generation on cells causes changes in chromatin organization, in most cases chromatin decondensation, that is coincident with changes in gene expression. 9,45,49,98 Similarly, nucleolar bodies are reorganized in response to substrate stiffness and force.…”

“…45,49 Other studies have shown that direct force generation on cells causes changes in chromatin organization, in most cases chromatin decondensation, that is coincident with changes in gene expression. 9,45,49,98 Similarly, nucleolar bodies are reorganized in response to substrate stiffness and force. 67 The mechanisms by which altered extracellular force or cytoskeletal force impact altered chromatin condensation are still being elucidated.…”

“…1) that result in changes in genome expression. 45,49 Remodeling can also come from forces imposed from outside of the cell such as compressive forces or fluid shear stress. 9 These stresses likely act globally and nonspecifically to increase chromatin agitation and, therefore, the probability of expression by enhancing the kinetic events of binding, remodeling, and the mobility of components.…”

“…9 These stresses likely act globally and nonspecifically to increase chromatin agitation and, therefore, the probability of expression by enhancing the kinetic events of binding, remodeling, and the mobility of components. 45,49,98 …”