The biology of syncytial cells: Dissecting the mechanisms and functions of nuclear differentiation inside skeletal muscle syncytium

Introduction

Due to their cellular anatomy, syncytial cells face many unique challenges that mono-nucleated cells do not. One of them is how syncytial cells organize gene expression among many nuclei in a shared cytoplasm. How such property is linked to their biological functions remains poorly understood.

Research Background

Using the skeletal muscle as a paradigm and single-nucleus transcriptomics, I recently uncovered previously unrecognized diversity and dynamics of myonuclear transcriptional programs. This conceptualized the syncytial muscle cell itself as an analog of multi-cellular tissue where individual nuclei are counterparts of differentiated cell types.

Key Questions

My findings raise two important and unanswered questions:

1. How are the diverse nuclear identities specified and maintained?
2. What are the functional contributions of the diverse nuclear subtypes in health and disease?

Focus Areas

I will first focus on the nuclei at the neuromuscular junction (NMJ) and myotendinous junction (MTJ), which are responsible for the initiation of contraction and dissipation of contractile force, respectively. Despite their well-established functions, the mechanisms that specify or maintain them are sparsely understood.

Investigation Plan

I will investigate how chromatin architecture and transcriptional regulators govern their identities. I will then characterize the upstream signaling pathways from motor neuron or tendon cells that activate the specific transcriptional programs.

Methodological Advances

So far, genetic manipulation of myofibers has targeted entire muscle nuclei. To overcome this limit, I will develop tools that allow genetic manipulation in specific nuclear subtypes. Previous works had identified a new nuclear subtype associated with muscular dystrophy and a transient time window during postnatal development.

Future Directions

I will characterize the function of these nuclei using a method that abolishes their transcriptional activities. The approaches to be developed here will pave the way to understanding the pathophysiology of syncytial cells in the future.