Deep Invaginations of Nuclear Envelope Coordinate Spatial Organization of Chromatin in Epithelium

Elina Mäntylä, Sanna Korpela, Anna Rekonen, Sini Hakkola, Jenni Karttunen, Anni Pörsti, Sanni Erämies, Fábio Tadeu Arrojo Martins, Roselia Davidsson, Markus J.T. Ojanen, Satu A-M. Hakanen, Peipei Wang, Joonas Uusi-Mäkelä, Alice Anais Varlet, Maija Vihinen-Ranta, Daniel E. Conway, Keijo Viiri, Matti Nykter, Jan Lammerding, Teemu O. Ihalainen

Posted on: 2 June 2026

Preprint posted on 12 March 2026

Cell crowding in epithelial cells causes nuclear remodeling and the formation of Deep Invaginations of the Nuclear Envelope (DINEs).

Selected by Abby Hein

Categories: cell biology, molecular biology

Background

As the largest organelle of the cell, structural regulation of the nucleus is critical to maintain the cell’s ability to respond and adapt to mechanical force. Forces exerted on the nucleus contribute to cell migration, chromatin remodeling, differentiation, and tissue homeostasis.

Nuclear mechanosensitivity is dysregulated across several disease states, including cancers, muscular dystrophies, and cardiomyopathies. Abnormalities in nuclear shape are a major feature of such dysregulation and include nuclear blebs, wrinkles, and invaginations. However, the mechanistic consequences of these abnormalities on cellular homeostasis and gene regulation are still poorly understood.

In this preprint, Mäntylä and colleagues characterize a distinct class of abnormalities called DINEs (Deep Invaginations of the Nuclear Envelope), defined as deep invaginations of the nuclear envelope that extend inward from the basal surface of the nucleus. These structures were found to form during epithelial cell growth and maturation driven by cellular crowding. The authors present the surprising finding that DINEs are not dependent on tension from the cytoskeleton but are dependent on A-type lamins.

Key findings

Figure 1: (A) Confocal images of epithelial nuclei in vitro stained for Lamin A/C. (C) Expansion microscopy images of nuclei with DINEs at 5 min, 2 hr, and 7 days after seeding. (from Mäntylä et al. 2026, Fig. 1)

DINEs are a distinct nuclear abnormality that form in the mature epithelium

ral abnormality that they observed during epithelial maturation in vitro: DINEs. DINEs are defined as invaginations that extend longitudinally across the nucleus and protrude from the basal surface of the nucleus, through at least half the diameter of the nucleus.

Through expansion microscopy and transmission electron microscopy, the authors observed that DINEs become prevalent as the cells grow to a mature monolayer and that they are flanked by densely packed chromatin. Interestingly, DINE-containing nuclei showed no significant difference in nuclear area or volume. Additionally, the authors found similar architectural abnormalities in epithelial cells in vivo, mouse esophagus and duodenum tissues as well as human esophageal and mouse intestinal organoids.

DINEs arise as a result of cellular confinement and are A-type Lamin dependent.

The authors observed that DINEs were more prevalent in vitro in confluent monolayers, and that spatially confined cells had higher DINE frequency. Furthermore, the authors conducted a lateral compression experiment by growing cells on a stretched PDMS membrane and then relaxing the membrane to introduce compressive strain. They found that lateral strain caused a 30% increase in the proportion of DINE-containing nuclei. The authors found that DINEs appear to be insensitive to cytoskeletal force, as DINE prevalence was not decreased by actin, microtubule, or intermediate filament depolymerization. However, DINE formation was completely ablated by knocking out Lamin A/C, a key component of the nuclear lamina and regulator of nuclear stiffness.

DINE formation correlates with downregulation of MAPK signaling, and MAPK suppression induces DINE formation

By total mRNA-seq, the authors observed that DINE formation in vitro correlates with the downregulation of several MAPK signaling pathway genes. They then treated cells with the MEK1/2 inhibitor, U0126, to suppress MAPK signaling. Upon this U0126 treatment, the authors observed a significant increase in the proportion of DINE-containing nuclei even at low cell density.

What I like about this preprint

This preprint describes an interesting example of how mechanical cues contribute to nuclear morphology and structural remodeling. I really liked this preprint because the authors present a thorough body of work that characterizes a unique type of nuclear abnormality and teases apart the factors that correlate with DINE formation, both genetic and mechanical. There is so much we still don’t understand about the mechanistic causes of different nuclear abnormalities and their direct effect on the cell state, so the authors’ case for cell crowding and compression inducing DINE formation is an interesting insight into how mechanical cues are felt in the nucleus. This work raises an interesting possibility of DINE formation as an example of a functional nuclear architecture feature that forms by a nuclear-intrinsic mechanism.

Discussion points/ Questions for the authors

You observed that lamin organization in DINEs is similar to the basal surface of the nuclear envelope. Does this indicate that the lamina within the DINE feels the same amount of force as the basal side of the nucleus, and how would this force be transmitted?
What is the timescale of DINE formation? Is there any link between DINE formation and cell cycle stage?
Lamin A/C expression levels have been found to be regulated by cellular compression in the epithelium.¹ Are there changes in lamin A/C expression that correlate with the formation of DINEs during differentiation? Additionally, do cells expressing polymerization-deficient lamin A form DINEs?

References:

1- Iyer, K.V., Taubenberger, A., Zeidan, S.A. et al. Apico-basal cell compression regulates Lamin A/C levels in epithelial tissues. Nat Commun 12, 1756 (2021). https://doi.org/10.1038/s41467-021-22010-9

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