The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo.

Jayson J. Smith,David Q. Matus,Michael A. Q. Martinez,Nicholas J. Palmisano,Kailong Wen,Abraham Q. Kohrman,Yutong Xiao,Rebecca C. Adikes,Nithin Parsan,Simeiyun Liu,Paschalis Kratsios,Wan Zhang,Sydney A. Bracht,Frances E. Q. Moore,Taylor N. Medwig-Kinney,Mana Chandhok Delos Reyes

doi:10.1371/journal.pgen.1009981

Abstract

Chromatin remodelers such as the SWI/SNF complex coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in genes encoding the structural subunits of chromatin, such as histone subunits, and chromatin regulating factors are associated with a variety of disease mechanisms including cancer metastasis, in which cancer co-opts cellular invasion programs functioning in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin agents and chromatin regulating factors that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and enhanced RNA interference (RNAi) vectors, we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Our data specifically implicate the SWI/SNF BAF assembly in the regulation of the G0 cell cycle arrest in the AC, whereas the SWI/SNF PBAF assembly promotes AC invasion via cell cycle-independent mechanisms, including attachment to the basement membrane (BM) and activation of the pro-invasive fos-1/FOS gene. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into how the SWI/SNF assemblies differentially contribute to cellular invasion and how SWI/SNF subunit-specific disruptions may contribute to tumorigeneses and cancer metastasis.

Highlights

Cellular invasion through basement membranes (BMs) is a critical step in metazoan development and is important for human health and fitness
Invasion programs are orchestrated by complex gene regulatory networks (GRN) that function in a coordinated fashion to turn on and off pro-invasive genes
To identify the suite of pro-invasive chromatin remodelers, we paired high resolution imaging with RNA interference to individually knockdown 269 chromatin factors, identifying the evolutionarily conserved SWItching defective/Sucrose Non-Fermenting (SWI/SNF) ATP-dependent chromatin remodeling complex as a new regulator of Caenorhabditis elegans anchor cell (AC) invasion

Summary

Introduction

Cellular invasion through basement membranes (BMs) is a critical step in metazoan development and is important for human health and fitness. A variety of in vitro and in vivo models have been developed to study the process of cellular invasion at the genetic and cellular levels. In vitro invasion assays typically involve 3D hydrogel lattices, such as Matrigel, through which cultured metastatic cancer cells will invade in response to chemo-attractants [7]. While in vitro invasion models provide an efficient means to study the mechanical aspects of cellular invasion, they are currently unable to replicate the complex microenvironment in which cells must invade during animal development and disease. Over the past ~15 years, Caenorhabditis elegans anchor cell (AC) invasion has emerged as a powerful alternative model due to its visually tractable single-cell nature (Fig 1A) [14]

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Conclusion