# Remodeling of the structure and function of the nuclear lamina by LINC complex-dependent tension

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $335,000

## Abstract

SUMMARY
The nuclear lamina is a compositionally complex structure that serves functions in chromatin organization,
transcriptional regulation, genome protection and mechanotransduction. In cells and tissues, the nuclear
lamina is mechanically integrated into the actin, microtubule, and intermediate filament cytoskeletons via
nuclear envelope-spanning Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes. Through these
cytoskeletal connections, forces exerted on plasma membrane adhesions from either the extracellular matrix or
from adjacent cells can be transmitted to the nuclear interior. In cells in which LINC complex function has been
altered, investigators have observed correlative changes in gene regulation. However, to date it has been
extremely challenging to decipher whether mechanical forces transmitted by the LINC complex, potentially
through interactions at the nuclear lamina, directly influence specific genetic programs. Our published work and
preliminary studies demonstrate that the LINC complex enables a critical crosstalk between cellular adhesions,
the cytoskeleton, and components of the nuclear periphery. Most important for this proposal, we used a mouse
model to reveal that A-type lamins and the LINC complex drive opposite effects on pro-fibrotic signaling, which
is classically driven by SMAD-dependent signaling downstream of TGFβ. Taking these insights together with
our global transcriptome studies, we suggest that tension exerted on the nuclear lamina by the LINC complex
influences nuclear events necessary for SMAD gene targets to be properly regulated by TGFβ inputs (despite
normal cytoplasmic events necessary to drive this signaling pathway). Building on this, here we propose three
complementary Aims that will address both molecular mechanisms as well as physiological contexts in which
these mechanisms play critical roles. First, we will take an unbiased approach to define how the LINC complex,
in combination with substrate inputs from the extracellular matrix, influences the nuclear lamina interactome in
situ, ultimately employing a cross-linking mass spectrometry approach. Second, we will investigate the
mechanisms by which LINC complex ablation influences SMAD function in the nucleus, including the analysis
of SMAD target binding, nuclear position of SMAD target genes, and the influence of integral inner nuclear
membrane proteins on SMAD-dependent gene output. Lastly, we will test if (and how) LINC complex function
intersects with that of A-type lamins in this TGFβ–SMAD-fibrotic axis using both in vitro and in vivo
approaches, including mouse models of interstitial fibrosis of the myocardium and lung injury models of
pulmonary fibrosis. Taken together, the Aims of this proposal will reveal both molecular mechanisms of
mechanotransduction through the LINC complex while also placing this detailed understanding into its
physiological and disease contexts.

## Key facts

- **NIH application ID:** 10247783
- **Project number:** 5R01GM129308-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** MEGAN C KING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,000
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247783

## Citation

> US National Institutes of Health, RePORTER application 10247783, Remodeling of the structure and function of the nuclear lamina by LINC complex-dependent tension (5R01GM129308-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247783. Licensed CC0.

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