About

Francisco J. Naya is an Associate Professor of Biology and the Director of Graduate Studies at Boston University. His research focuses on gene regulation in muscle development and disease, utilizing a systems-level approach to investigate complex gene regulatory networks involved in cardiac and skeletal muscle differentiation. His work emphasizes understanding the role of noncoding RNAs, including microRNAs, small nucleolar RNAs, and long noncoding RNAs, in muscle differentiation, regeneration, and disease mechanisms. Naya's research has identified the significance of the Dlk1-Dio3 noncoding RNA locus in skeletal muscle differentiation, regeneration, and cardiomyocyte proliferation. He has demonstrated that the long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial mesenchymal transition, and that the entire Dlk1-Dio3 ncRNA cluster coordinates mitochondrial metabolism and chromatin structure to maintain proper myogenic cell states. His ongoing investigations utilize genome-wide transcriptomic and genomic approaches to elucidate the multifunctional gene regulatory roles of this imprinted ncRNA locus.

Research topics

• Cell biology
• Biology
• Genetics
• Neuroscience
• Cardiology
• Chemistry
• Medicine
• Physics
• Endocrinology

Selected publications

• Virally delivered CMYA5 enhances the assembly of cardiac dyads

  Nature Biomedical Engineering · 2024-09-05 · 3 citations

  articleOpen access
  PublisherOA PDFDOI

• The <i>Dlk1-Dio3</i> noncoding RNA cluster coordinately regulates mitochondrial respiration and chromatin structure to establish proper cell state for muscle differentiation

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-22

  preprintOpen accessSenior authorCorresponding

  Abstract The coordinate regulation of metabolism and epigenetics to establish cell state-specific gene expression patterns during lineage progression is a central aspect of cell differentiation, but the factors that regulate this elaborate interplay are not well-defined. The imprinted Dlk1-Dio3 noncoding RNA (ncRNA) cluster has been associated with metabolism in various progenitor cells, suggesting it functions as a regulator of metabolism and cell state. Here, we directly demonstrate that the Dlk1-Dio3 ncRNA cluster coordinates mitochondrial respiration and chromatin structure to maintain proper cell state. Stable muscle cell lines were generated harboring two distinct deletions in the proximal promoter region resulting in either greatly upregulated or downregulated expression of the entire Dlk1-Dio3 ncRNA cluster. Both mutant lines displayed impaired muscle differentiation along with altered mitochondrial respiration and genome-wide changes in chromatin accessibility and histone methylation. Global gene expression patterns and pathway analyses indicated a reprogramming of myogenic cell state creating a differentiated-like phenotype in proliferating myoblasts. Our results strongly suggest the Dlk1-Dio3 ncRNA locus is a nodal regulator coordinating metabolic activity and the epigenome to maintain proper cell state in the myogenic lineage. Summary statement Muscle cell state is regulated by the imprinted Dlk1-Dio3 noncoding RNA locus through its coordinate control of mitochondrial activity and histone modifications.

  PublisherOA PDFDOI

• The <i>Dlk1-Dio3</i> noncoding RNA cluster coordinately regulates mitochondrial respiration and chromatin structure to establish proper cell state for muscle differentiation

  Development · 2024-11-29 · 3 citations

  articleSenior author

  The coordinate regulation of metabolism and epigenetics to establish cell state-specific gene expression patterns during lineage progression is a central aspect of cell differentiation, but the factors that regulate this elaborate interplay are not well-defined. The imprinted Dlk1-Dio3 noncoding RNA (ncRNA) cluster has been associated with metabolism in various progenitor cells, suggesting it functions as a regulator of metabolism and cell state. Here, we directly demonstrate that the Dlk1-Dio3 ncRNA cluster coordinates mitochondrial respiration and chromatin structure to maintain proper cell state. Stable mouse muscle cell lines were generated harboring two distinct deletions in the proximal promoter region, resulting in either greatly upregulated or downregulated expression of the entire Dlk1-Dio3 ncRNA cluster. Both mutant lines displayed impaired muscle differentiation along with dysregulated structural gene expression and abnormalities in mitochondrial respiration. Genome-wide chromatin accessibility and histone methylation patterns were also severely affected in these mutants. Our results strongly suggest that muscle cells are sensitive to Dlk1-Dio3 ncRNA dosage, and that the cluster coordinately regulates metabolic activity and the epigenome to maintain proper cell state in the myogenic lineage.

  PublisherDOI

• CMYA5 establishes cardiac dyad architecture and positioning

  Nature Communications · 2022 · 37 citations

  • Cell biology
  • Biology
  • Chemistry

  release.

  PublisherOA PDFDOI

• The Key Lnc (RNA)s in Cardiac and Skeletal Muscle Development, Regeneration, and Disease

  Journal of Cardiovascular Development and Disease · 2021-07-25 · 17 citations

  reviewOpen accessSenior authorCorresponding

  Non-coding RNAs (ncRNAs) play a key role in the regulation of transcriptional and epigenetic activity in mammalian cells. Comprehensive analysis of these ncRNAs has revealed sophisticated gene regulatory mechanisms which finely tune the proper gene output required for cellular homeostasis, proliferation, and differentiation. However, this elaborate circuitry has also made it vulnerable to perturbations that often result in disease. Among the many types of ncRNAs, long non-coding RNAs (lncRNAs) appear to have the most diverse mechanisms of action including competitive binding to miRNA targets, direct binding to mRNA, interactions with transcription factors, and facilitation of epigenetic modifications. Moreover, many lncRNAs display tissue-specific expression patterns suggesting an important regulatory role in organogenesis, yet the molecular mechanisms through which these molecules regulate cardiac and skeletal muscle development remains surprisingly limited. Given the structural and metabolic similarities of cardiac and skeletal muscle, it is likely that several lncRNAs expressed in both of these tissues have conserved functions in establishing the striated muscle phenotype. As many aspects of regeneration recapitulate development, understanding the role lncRNAs play in these processes may provide novel insights to improve regenerative therapeutic interventions in cardiac and skeletal muscle diseases. This review highlights key lncRNAs that function as regulators of development, regeneration, and disease in cardiac and skeletal muscle. Finally, we highlight lncRNAs encoded by imprinted genes in striated muscle and the contributions of these loci on the regulation of gene expression.

  PublisherOA PDFDOI

• The long noncoding RNA <i>Meg3</i> regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition

  Development · 2020 · 26 citations

  Senior authorCorresponding
  • Biology
  • Cell biology
  • Endocrinology

  regulates myoblast identity to facilitate progression into differentiation.

  PublisherDOI

• Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart

  Nature Communications · 2020 · 24 citations

  • Cell biology
  • Biology
  • Medicine

  Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinβ, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinβ in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinβ mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinβ knock-out mice-indicating a functional and genetic interaction between Xinβ and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.

  PublisherOA PDFDOI

• The long noncoding RNA <i>Meg3</i> regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-06-15 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Formation of skeletal muscle is among the most striking examples of cellular plasticity in animal tissue development, where mononucleated, lineage-restricted progenitor cells are reprogrammed by epithelial-mesenchymal transition (EMT) to produce multinucleated myofibers. While some mediators of EMT have been shown to function in muscle formation, the regulation of this process in this tissue remains poorly understood. The long noncoding RNA (lncRNA) Meg3 is processed from the &gt;200 kb Dlk1-Dio3 polycistron that we have previously shown is involved in skeletal muscle differentiation and regeneration. Here, we demonstrate that Meg3 regulates EMT in myoblast differentiation and skeletal muscle regeneration. Chronic inhibition of Meg3 in C2C12 myoblasts promoted aberrant EMT activation, and suppressed cell state transitions required for fusion and myogenic differentiation. Furthermore, adenoviral Meg3 knockdown compromised muscle regeneration, which was accompanied by abnormal mesenchymal gene expression and interstitial cell proliferation in the regenerating milieu. Transcriptomic and pathway analyses of Meg3 -depleted C2C12 myoblasts and injured skeletal muscle revealed a significant dysregulation of EMT-related genes, and identified TGFβ as a key upstream regulator. Importantly, chemical inhibition of TGFβR1, as well as its downstream effectors ROCK1/2 and p38 MAPK, restored many aspects of myogenic differentiation in Meg3 -depleted myoblasts in vitro . Thus, Meg3 regulates myoblast identity to maintain proper cell state for progression into differentiation. Summary statement Muscle differentiation and regeneration are regulated by an evolutionarily conserved long noncoding RNA that restricts gene expression to coordinate cell state transitions

  PublisherOA PDFDOI

• ERK Regulates NeuroD1-mediated Neurite Outgrowth via Proteasomal Degradation

  Experimental Neurobiology · 2020-06-30 · 19 citations

  articleOpen access

  Neurogenic differentiation 1 (NeuroD1) is a class B basic helix-loop-helix (bHLH) transcription factor and regulates differentiation and survival of neuronal and endocrine cells by means of several protein kinases, including extracellular signal-regulated kinase (ERK). However, the effect of phosphorylation on the functions of NeuroD1 by ERK has sparked controversy based on context-dependent differences across diverse species and cell types. Here, we evidenced that ERK-dependent phosphorylation controlled the stability of NeuroD1 and consequently, regulated proneural activity in neuronal cells. A null mutation at the ERK-dependent phosphorylation site, S274A, increased the half-life of NeuroD1 by blocking its ubiquitin-dependent proteasomal degradation. The S274A mutation did not interfere with either the nuclear translocation of NeuroD1 or its heterodimerization with E47, its ubiquitous partner and class A bHLH transcription factor. However, the S274A mutant increased transactivation of the E-box-mediated gene and neurite outgrowth in F11 neuroblastoma cells, compared to the wild-type NeuroD1. Transcriptome and Gene Ontology enrichment analyses indicated that genes involved in axonogenesis and dendrite development were downregulated in NeuroD1 knockout (KO) mice. Overexpression of the S274A mutant salvaged neurite outgrowth in NeuroD1-deficient mice, whereas neurite outgrowth was minimal with S274D, a phosphomimicking mutant. Our data indicated that a longer protein half-life enhanced the overall activity of NeuroD1 in stimulating downstream genes and neuronal differentiation. We propose that blocking ubiquitin-dependent proteasomal degradation may serve as a strategy to promote neuronal activity by stimulating the expression of neuron-specific genes in differentiating neurons.

  PublisherOA PDFDOI

• Altered dosage of noncoding RNAs expressed from the <i>Dlk1‐Dio3</i> locus impairs skeletal muscle differentiation

  The FASEB Journal · 2019-04-01

  articleSenior author

  Noncoding RNAs (ncRNAs) have emerged as key components of gene regulatory networks, yet their role in skeletal muscle diseases is still poorly understood. The maternally imprinted Dlk1 ‐ Dio3 ncRNA locus has been shown to play an essential role in skeletal muscle development, regeneration, and metabolism. The diverse ncRNAs expressed from this locus, including over 50 microRNAs (miRNAs), several long noncoding RNAs (lncRNAs), and a cluster of C/D box snoRNAs, are thought to be transcribed as a ~200 kb polycistron initiating from the proximal promoter immediately upstream of the Gtl2 lncRNA, the most 5′ ncRNA in the locus. This project aimed to understand the importance of proper dosage of the Dlk1‐Dio3 ncRNAs in skeletal muscle differentiation. Toward this end, we utilized CRISPR‐Cas9 gene editing to generate deletions in the Gtl2 proximal promoter and the overlapping differentially methylated region (DMR) with the goal of modulating expression of the maternally expressed ncRNAs in C2C12 myoblasts, an established muscle cell line. This gene editing strategy yielded a clonal population of C2C12 myoblasts that harbored a deletion spanning a portion of the Gtl2 proximal promoter while leaving the Gtl2 promoter's TATA box intact. This CRISPR‐edited cell line showed a dramatic increase in the Dlk1‐Dio3 ncRNAs. As a result of Dlk1‐Dio3 ncRNA upregulation, this C2C12 cell line displays significantly impaired myogenic differentiation. The continued characterization of this novel C2C12 cell line will help elucidate the importance of maintaining proper dosage of the Dlk1‐Dio3 locus in skeletal muscle, which could serve as a therapeutic target for treating muscle diseases. Support or Funding Information This project was supported with funds from the Arnold &amp; Mabel Beckman Foundation and the Boston University Undergraduate Research Opportunities Program This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

  PublisherDOI

Recent grants

• MEF2 Function in Cardiac Muscle Development

  NIH · $3.3M · 2003–2016

Frequent coauthors

• Ming‐Jer Tsai

  National Tsing Hua University

  21 shared

• Andrew B. Leiter

  17 shared

• H. Mutoh

  Hokuriku Electric Power Company (Japan)

  9 shared

• Hiroyuki Mutoh

  The University of Tokyo

  8 shared

• Christine Snyder

  7 shared

• Sarah A. McCalmon

  Pacific Biosciences (United States)

  7 shared

• William T. Pu

  Boston Children's Hospital

  7 shared

• Junko Nishitani

  6 shared