Dr. Francesca Briganti is a molecular biologist interested in understanding the molecular causes of human diseases and in using this knowledge to design targeted therapeutic strategies. She is a postdoctoral scholar in the Mercola lab. She is extending her training in the cardiac physiology, high-throughput screenings, and drug development.
Dr. Briganti received her PhD jointly from the European Molecular Biology Laboratory and the University of Heidelberg. During her PhD she studied new targeted therapeutic approaches for Dilated Cardiomyopathy. She identified a new potential therapeutic strategy that has been published and patented.
Dr. Briganti received her B.Sc and M. Sc in Genetics and Molecular Biology with honors from the University of Rome La Sapienza, Rome, Italy. During a three years internship in Prof. Bozzoni's lab she studied the role of alternative splicing modulation in the pathogenesis and treatment of Duchenne Muscular Dystrophy.
Doctor of Philosophy, Ruprecht Karl Universitat Heidelberg (2018)
Master of Science, Universita Degli Studi Di Roma (2014)
Bachelor of Science, Universita Degli Studi Di Roma (2012)
Current Research and Scholarly Interests
One gene can lead to the production of many different RNA isoforms via mechanisms such as alternative promoter usage, splicing, and polyadenylation. The functional significance of many of these isoforms, their impact on cell physiology, and their regulation remain mostly controversial. Understanding the functional consequences of transcript heterogeneity will improve our understanding of gene expression regulation, broadening our ability to intervene when mutations that interfere with this regulation cause human disease.
My goal is to become an independent researcher leading an academic lab that focuses on better understanding human tissue-specific post-transcriptional regulation of gene expression and developing mechanism-based therapeutics. My general strategy is to study the function of regulatory genes and their deregulation in human disease. My specific approach is to understand the molecular mechanisms by which disease-causing mutations alter the gene function and lead to human disease. My hypothesis is that a detailed understanding of the relationship between the gene's molecular function and the disease mechanism will allow the development of first-in-class, personalized therapeutic strategies that target the disease mechanisms rather than manage symptoms independently of disease etiology.
- Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs (vol 26, pg 1788, 2020) NATURE MEDICINE 2021
Human iPSC modeling of heart disease for drug development.
Cell chemical biology
2021; 28 (3): 271–82
Human induced pluripotent stem cells (hiPSCs) have emerged as a promising platform for pharmacogenomics and drug development. In cardiology, they make it possible to produce unlimited numbers of patient-specific human cells that reproduce hallmark features of heart disease in the culture dish. Their potential applications include the discovery of mechanism-specific therapeutics, the evaluation of safety and efficacy in a human context before a drug candidate reaches patients, and the stratification of patients for clinical trials. Although this new technology has the potential to revolutionize drug discovery, translational hurdles have hindered its widespread adoption for pharmaceutical development. Here we discuss recent progress in overcoming these hurdles that should facilitate the use of hiPSCs to develop new medicines and individualize therapies for heart disease.
View details for DOI 10.1016/j.chembiol.2021.02.016
View details for PubMedID 33740432
Single-molecule, full-length transcript isoform sequencing reveals disease-associated RNA isoforms in cardiomyocytes.
2021; 12 (1): 4203
Alternative splicing generates differing RNA isoforms that govern phenotypic complexity of eukaryotes. Its malfunction underlies many diseases, including cancer and cardiovascular diseases. Comparative analysis of RNA isoforms at the genome-wide scale has been difficult. Here, we establish an experimental and computational pipeline that performs de novo transcript annotation and accurately quantifies transcript isoforms from cDNA sequences with a full-length isoform detection accuracy of 97.6%. We generate a searchable, quantitative human transcriptome annotation with 31,025 known and 5,740 novel transcript isoforms ( http://steinmetzlab.embl.de/iBrowser/ ). By analyzing the isoforms in the presence of RNA Binding Motif Protein 20 (RBM20) mutations associated with aggressive dilated cardiomyopathy (DCM), we identify 121 differentially expressed transcript isoforms in 107 cardiac genes. Our approach enables quantitative dissection of complex transcript architecture instead of mere identification of inclusion or exclusion of individual exons, as exemplified by the discovery of IMMT isoforms mis-spliced by RBM20 mutations. Thereby we achieve a path to direct differential expression testing independent of an existing annotation of transcript isoforms, providing more immediate biological interpretation and higher resolution transcriptome comparisons.
View details for DOI 10.1038/s41467-021-24484-z
View details for PubMedID 34244519
Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes.
2020; 32 (3): 107925
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders. However, their physiological immaturity severely limits their utility as a model system and their adoption for drug discovery. Here, we describe maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs. Compared with conventionally cultured hiPSC-CMs, metabolically matured hiPSC-CMs contract with greater force and show an increased reliance on cardiac sodium (Na+) channels and sarcoplasmic reticulum calcium (Ca2+) cycling. The media enhance the function, long-term survival, and sarcomere structures in engineered heart tissues. Use of the maturation media made it possible to reliably model two genetic cardiac diseases: long QT syndrome type 3 due to a mutation in the cardiac Na+ channel SCN5A and dilated cardiomyopathy due to a mutation in the RNA splicing factor RBM20. The maturation media should increase the fidelity of hiPSC-CMs as disease models.
View details for DOI 10.1016/j.celrep.2020.107925
View details for PubMedID 32697997
Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs.
Ribonucleoprotein (RNP) granules are biomolecular condensates-liquid-liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation.
View details for DOI 10.1038/s41591-020-1087-x
View details for PubMedID 33188278
iPSC Modeling of RBM20-Deficient DCM Identifies Upregulation of RBM20 as a Therapeutic Strategy.
2020; 32 (10): 108117
Recent advances in induced pluripotent stem cell (iPSC) technology and directed differentiation of iPSCs into cardiomyocytes (iPSC-CMs) make it possible to model genetic heart disease in vitro. We apply CRISPR/Cas9 genome editing technology to introduce three RBM20 mutations in iPSCs and differentiate them into iPSC-CMs to establish an in vitro model of RBM20 mutant dilated cardiomyopathy (DCM). In iPSC-CMs harboring a known causal RBM20 variant, the splicing of RBM20 target genes, calcium handling, and contractility are impaired consistent with the disease manifestation in patients. A variant (Pro633Leu) identified by exome sequencing of patient genomes displays the same disease phenotypes, thus establishing this variant as disease causing. We find that all-trans retinoic acid upregulates RBM20 expression and reverts the splicing, calcium handling, and contractility defects in iPSC-CMs with different causal RBM20 mutations. These results suggest that pharmacological upregulation of RBM20 expression is a promising therapeutic strategy for DCM patients with a heterozygous mutation in RBM20.
View details for DOI 10.1016/j.celrep.2020.108117
View details for PubMedID 32905764
Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis
2017; 66 (1): 22-+
Circular RNAs (circRNAs) constitute a family of transcripts with unique structures and still largely unknown functions. Their biogenesis, which proceeds via a back-splicing reaction, is fairly well characterized, whereas their role in the modulation of physiologically relevant processes is still unclear. Here we performed expression profiling of circRNAs during in vitro differentiation of murine and human myoblasts, and we identified conserved species regulated in myogenesis and altered in Duchenne muscular dystrophy. A high-content functional genomic screen allowed the study of their functional role in muscle differentiation. One of them, circ-ZNF609, resulted in specifically controlling myoblast proliferation. Circ-ZNF609 contains an open reading frame spanning from the start codon, in common with the linear transcript, and terminating at an in-frame STOP codon, created upon circularization. Circ-ZNF609 is associated with heavy polysomes, and it is translated into a protein in a splicing-dependent and cap-independent manner, providing an example of a protein-coding circRNA in eukaryotes.
View details for PubMedID 28344082
View details for PubMedCentralID PMC5387670
The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype
2016; 7: 10488
Substitutions, deletions and duplications in the dystrophin gene lead to either the severe Duchenne muscular dystrophy (DMD) or mild Becker muscular dystrophy depending on whether out-of-frame or in-frame transcripts are produced. We identified a DMD case (GSΔ44) where the correlation between genotype and phenotype is not respected, even if carrying a typical Duchenne mutation (exon 44 deletion) a Becker-like phenotype was observed. Here we report that in this patient, partial restoration of an in-frame transcript occurs by natural skipping of exon 45 and that this is due to the lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those DMD therapeutic treatments, which requires exon 45 skipping.
View details for DOI 10.1038/ncomms10488
View details for Web of Science ID 000369031500001
View details for PubMedID 26796035
View details for PubMedCentralID PMC4736020