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## Overview

#### Senior Investigator

Vittorio Sartorelli, M.D.

sartorev@mail.nih.gov

#### Research Areas (IRP Lab Groups)

Cell Biology

Chromosome Biology

Computational Biology

Developmental Biology

Genetics and Genomics

Muscle Biology

Stem Cell Biology

Skeletal muscle hosts stem cells (called Muscle Stem Cells or MuSCs) that sustain muscle growth, preserve homeostasis, and repair injuries occurring in muscle degenerative disease or trauma. Our laboratory studies how MuSCs acquire their identity during development and how their behavior is regulated during muscle regeneration and aging. We approach these questions by generating, analyzing, and integrating genomic, epigenomic, transcriptomic, and metabolomic datasets.

## Areas of Interest

Specific areas of interest include:

### **Transcriptional Regulation of Skeletal Muscle Differentiation**

Our research considers the biochemical and molecular characterization of individual transcription factors, chromatin regulators, and epigenetic marks during skeletal muscle specification and development. The genetic manipulation of the individual components is obtained by whole-body and conditional gene ablation in developing embryos and adult mice.

### **Regulatory Circuitry in Skeletal Muscle Cells**

We study the integration of signaling pathways and the logics of transcription factors and chromatin regulators. We develop general operating principles and conduct gene network modeling based on genome-wide experimental data.

### **Regeneration of Adult Skeletal Muscle**

Following injury, skeletal muscle vigorously regenerates. We investigate the cellular and molecular mechanisms underlying regeneration in animals in which individual genetic components have been ablated by homologous recombination.

### **Metabolic Regulation of Epigenetics**

As satellite cells exit from quiescence during muscle regeneration, they are accompanied by changes in their metabolic state. We investigate the molecular connection between metabolism and epigenetic modification of chromatin that accompanies the transition from quiescence to proliferation and differentiation of muscle precursors.

The ultimate goal of our studies is to provide a conceptual and practical framework contributing to the diagnosis and treatment of human diseases affecting skeletal muscles.

#### Related NIAMS Labs

                                    - Muscle Disease Unit
                                    - RNA Molecular Biology Laboratory

#### Scientific Advances

August 16, 2022

Molecular Mechanisms Leading to the Formation of Muscle and Neuronal Cells Starting from Mouse Embryonic Stem Cells

June 8, 2022

Isolation and Culture of Muscle Stem Cells and Progenitor Cells

#### Core Research Facilities

Labs at the NIAMS are supported by the following state-of-the-art facilities and services:
                                        - Biodata Mining and Discovery
                                        - Flow Cytometry
                                        - Genomic Technology
                                        - Laboratory Animal Care and Use
                                        - Light Imaging
                                        - Translational Immunology

## Staff

**Vittorio Sartorelli, M.D.**

sartorev@mail.nih.gov

**Natalia Acevedo Luna, Ph.D.**

natalia.acevedoluna@nih.gov

**Veronica Ciuffoli, Ph.D.**

veronica.ciuffoli@nih.gov

**Xuesong Feng **

fengx4@mail.nih.gov 

**Mamduh Khateb, Ph.D.**

mamduh.khateb@nih.gov

**Kyung Dae Ko **

kok3@mail.nih.gov 

**Morgan Mackenzie, B.S., B.A.**

morgan.mackenzie@nih.gov

**Giulia Riparini, Ph.D.**

giulia.riparini@nih.gov

**Hong Jun Wang, Ph.D.**

hongjun.wang@nih.gov

**Job Vacancy:** Postdoctoral positions are immediately available in the Laboratory of Muscle Stem Cells and Gene Regulation (LMSCGR) at NIAMS of the National Institutes of Health, Bethesda, MD, USA. Ambitious and strongly motivated individuals with a solid background in molecular biology (bioinformatics is desirable but not required) are invited to apply.

## Former Lab Members

### Postdoctoral Fellows

                            - Jelena Perovanovic, Ph.D. (2016-2019) Computational Biologist, Recursion, Salt Lake City, UT
                            - Pei-Fang Tsai, Ph.D. (2014-2018) Principal Scientist, Fate Therapeutics Inc., San Diego, CA
                            - Alessandra Pasut, Ph.D. (2015-2017) Senior Scientist, Center for Cancer Biology, Leuven, Belgium
                            - Aster H. Juan, Ph.D. (2009-2014), Scientific Review Officer, CSR, NIH
                            - James G. Ryall, Ph.D. (2009-2014) Chief Scientific Officer, Vow Food, Sydney, Australia
                            - Stefania Dell’Orso, Ph.D. (2009-2014) Chief, NIAMS Genomic Technology Section
                            - Miroslav Koulnis, Ph.D. (2011-2013) Scientist, Sony Biotechnology, Boston, MA
                            - Kambiz Mousavi, Ph.D. (2008-2013) Senior Scientist, Moderna Therapeutics, Cambridge, MA
                            - Monica Di Padova, Ph.D. (2004-2008) Assistant Professor, Department of Experimental Medicine, University of L’Aquila, Italy
                            - Shanil Haugen, Ph.D. (2005-2008) Staff Fellow, US Food and Drug Administration
                            - Giuseppina Caretti, Ph.D. (2002-2007) Associate Professor, Department of Genetics, University of Milan, Italy
                            - Gabriella Fiore, Ph.D. (2003-2006) Research Associate, Comparative Genomic Center, James Cook University, Townsville, Australia
                            - R. Louis Schiltz, Ph.D. (2000-2005) Biologist, Laboratory of Receptor Biology and Gene Expression, NCI
                            - Simona Iezzi, Ph.D. (2000-2004) Staff Scientist, Regina Elena Cancer Center, Rome, Italy
                            - Frederic Lluís Vinas (2004) Professor, Katholieke Universiteit Leuven, Belgium
                            - Antonio Costanzo, M.D. (2000) Professor, Humanitas University, Milan, Italy

### Postbaccalaureate Fellows

                            - Aissah “Mama” Kaba, B.S. (2019-2021) Master of Translational Medicine student, UC Berkeley
                            - Christopher Lopez, B.S. (2019-2021) MD/Ph.D. Student Stanford University
                            - Stan Wang, M.D., Ph.D. (2014-2017) CEO, Stealth Cell Therapy, Non-Resident Senior Fellow Council of Strategic Risks
                            - Karinna Vivanco, B.S. (2015-2017) Graduate Student, UC Berkeley/UCSF Bioengineering Ph.D. Program
                            - Daphney Clermont, M.D., MPH (2013-2015), Pediatric Resident, Cardinal Glennon Children Hospital, St Louis, MO

## Image & Media Gallery

##### NIAMS Discovery on Stem Cell Development

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Stem Cell Development Video 

NIAMS researcher Dr. Vittorio Sartorelli led a team that found the protein Spt6 plays a key role in the development of embryonic stem cells. The study appears in the journal Molecular Cell. (Abstract is publicly available; access to the full paper requires payment or a subscription)

##### Redistribution and realignment of enlarged lysosomes

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Transcription factor EB (TFEB) promotes cellular clearance in lysosomal storage disorders by stimulating lysosomal exocytosis – a process of lysosomal docking/fusion with the plasma membrane followed by the discharge of excessive lysosomal storage outside the cell. The effect of TFEB was tested in acid alpha-glucosidase knockout mice, a model of glycogen storage disease type II, also known as Pompe disease. The image shows redistribution and realignment of enlarged lysosomes (red vesicles) along the plasma membrane - the telltale signs of TFEB’s effect - in a live muscle fiber transfected in vivo with mCherry-LAMP1 (lysosomal marker) and GFP-TFEB.

##### Molecular Cell Cover - Volume 51, Issue 5

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**Molecular Cell Cover - 12 September, 2013 Volume 51, Issue 5**Enhancers regulate gene expression. In addition to their role as recruiting platforms for transcription factors, enhancers are themselves transcribed into noncoding RNA (enhancer RNAs, eRNAs). The cover illustrates how coregulated genes (represented by the leaves of the tree) occupy specific chromatin domains and structures that ensure their coordinated expression, as described in Mousavi et al. (606–617). eRNAs (stylized as harpins) control expression of the gene of origin (red leaf) and of other coregulated genes (yellow and green leaves). Image concept by Vittorio Sartorelli and Kambiz Mousavi. Artwork by Ethan Tyler.

##### Histone variant macroH2A1.2

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Histone variant macroH2A1.2 marks the regulatory regions for gene activation in muscle cells and serves as a guide for chromatin recruitment of Pbx1 and subsequent binding of MyoD.

##### Resistant genes are associated with tightly packed chromatin

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**Top panel:** Resistant genes are associated with tightly packed chromatin (**left**). Microinjection of defined RNAs (**middle**) causes chromatin relaxation (**right**) and reactivation of resistant genes.**Bottom panel:** Microinjection of RNAs into cell nuclei.

##### Muscle Stem Cells and Gene Regulation Staff

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First row (left to right): Daphney Clermont, Aster Juan, Hongjun Wang, Stefania Dell'OrsoSecond row (left to right): Giuseppina Caretti, Raffaella Fittipaldi, Xuesong Feng, Benedetta Zaniboni, Kambiz Mousavi, Hossein Zare, Vittorio Sartorelli, Assia Derfoul

##### Skeletal Muscle Stem Cells

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##### Cellular and Molecular Mechanisms

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## Scientific Publications

## Selected Recent Publications

###             Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration.        

38(3-4).

###             A deep learning adversarial autoencoder with dynamic batching displays high performance in denoising and ordering scRNA-seq data.        

27(3).

###             HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients.        

30(3).

###             Polycomb Ezh1 maintains murine muscle stem cell quiescence through non-canonical regulation of Notch signaling.        

58(12).

###             Protocols to generate and isolate mouse myogenic progenitors both in vitro and in vivo.        

4(1).

###             The JAK-STAT pathway at 30: Much learned, much more to do.        

185(21).

###             Transcriptomics, regulatory syntax, and enhancer identification in mesoderm-induced ESCs at single-cell resolution.        

40(7).

###             Protocol for RNA-seq library preparation starting from a rare muscle stem cell population or a limited number of mouse embryonic stem cells.        

2(2).

###             Enhancers, gene regulation, and genome organization.        

35(7-8).

## Key Publications

### Transcriptomics, regulatory syntax, and enhancer identification in mesoderm-induced ESCs at single-cell resolution. 

40(7).

Scientific Advance

### FACS-isolation and Culture of Fibro-Adipogenic Progenitors and Muscle Stem Cells from Unperturbed and Injured Mouse Skeletal Muscle. 

(184).

Scientific Advance

### Single cell analysis of adult mouse skeletal muscle stem cells in homeostatic and regenerative conditions.

146(12).

### A Muscle-Specific Enhancer RNA Mediates Cohesin Recruitment and Regulates Transcription In trans.

71(1).

### Shaping Gene Expression by Landscaping Chromatin Architecture: Lessons from a Master.

71(3).

### The Elongation Factor Spt6 Maintains ESC Pluripotency by Controlling Super-Enhancers and Counteracting Polycomb Proteins.

68(2).

### Metabolic Reprogramming of Stem Cell Epigenetics.

17(6).

### The NAD(+)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells.

16(2).

### eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci.

51(5).

See all Publications on PubMed

## News & Highlights

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