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UC Irvine researchers investigate muscle cell development in muscular dystrophy

Posted: 2024-06-28

Source: UCI School of Medicine
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Muscle cells profiled using MERFISH reveal individual RNA locations and submicron resolution.


Irvine, Calif., June 28, 2024 — Facioscapulohumeral muscular dystrophy (FHSD) is one of the most common muscular dystrophies, which results in progressive weakening of skeletal muscles. The disease is linked to reactivation of the embryonic DUX4 transcription factor gene, which is normally epigenetically silenced in adult muscle. However, DUX4 expression is very rare (<1-2% of patient myocytes), and how its limited expression leads to FSHD pathogenesis remains enigmatic. 

Now, a new study published in Genome Research by UCI School of Medicine researchers utilize cutting-edge single-cell spatial transcriptomics to analyze gene expression in individual nuclei and myocytes of disease and control samples to determine how the disease state develops during human skeletal myocyte differentiation.

Co-led by Kyoko Yokomori, PhD, professor in the Department of Biological Chemistry, and Xiangmin Xu, PhD, Chancellor’s Professor of Anatomy and Neurobiology and director of the Center for Neural Circuit Mapping (CNCM), the research team employed the spatial transcriptomics technique known as multiplexed error-robust fluorescent in situ hybridization (MERFISH) to analyze in vitro differentiated FSHD patient, engineered mutant and isogenic control muscle cells.

MERFISH uniquely enables both cell and nucleus level analyses of muscle cells, which unlike most cells in the body, contain multiple nuclei. This study uncovers significant gene network disruption and rewiring in the majority of differentiating disease cells correlating with increased number of nuclei expressing DUX4 target gene sub pathways, providing evidence for DUX4 signal amplification.

This study has paved the way for future investigations and helped to formulate a new hypothesis that a small number of nuclei affected by the FHSD disease impact muscle cell development after muscle cell fusion, resulting in progressive muscle degeneration over time. On-going work is looking at patient biopsies to validate and expand the hypothesis and beginning to examine the contributions of non-muscle cells in the muscle microenvironment in the disease process.

Drs. Yokomori and Xu's innovative research was a collaborative effort, including contributions from Drs. Zhiqun Tan, Lujia Chen, Xiangduo Kong, and Kevin Johnston of the Yokomori and Xu labs. Other co-authors include Ali Mortazavi, PhD, professor in the Department of Biological Chemistry, and Todd C. Holmes, PhD, professor in the Department of Physiology and Biophysics.  Leveraging the CNCM’s collaborative infrastructure, the Center investigators have developed increasingly powerful technologies to probe the genetic mechanisms of neurodegenerative diseases. The Center resources have also helped other researchers to approach developing treatments for individuals affected by other diseases including muscular dystrophy. 

Read the full article, “Single-cell spatial transcriptomics reveals a dystrophic trajectory following a developmental bifurcation of myoblast cell fates in facioscapulohumeral muscular dystrophy in the new issue of Genome Research.

This study was supported in part by NIH R01AR071287.

About the UCI School of Medicine

Each year, the UCI School of Medicine educates more than 400 medical students and nearly 150 PhD and MS students. More than 700 residents and fellows are trained at the UCI Medical Center and affiliated institutions. Multiple MD, PhD and MS degrees are offered. Students are encouraged to pursue an expansive range of interests and options. For medical students, there are numerous concurrent dual degree programs, including an MD/MBA, MD/MPH, or an MD/MS degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Program in Medical Education for Leadership Education to Advance Diversity-African, Black and Caribbean (PRIME LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit