About

Sylvia Evans, Ph.D., is a professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences and also affiliated with the Department of Medicine at the School of Medicine. Her research focuses on defining genetic pathways underlying heart development and applying that understanding to both congenital and adult heart disease. A fundamental aspect of her work involves understanding the stepwise process by which mesodermal precursors become committed to cardiac progenitors and are specified into distinct cardiac lineages. Dr. Evans' lab has developed several Cre-expressing mouse models to examine gene pathways required for specific cardiac lineages, including the proepicardial organ, vasculature cells, and cardiac fibroblasts. Her academic background includes a B.S. in Genetics from the University of Alberta, a Ph.D. in Biochemistry from the University of British Columbia, and a postdoctoral fellowship in Neuromolecular Biology at The Salk Institute. She has received numerous awards and honors, such as the NIH Director’s Pioneer Award and the Cardiovascular NHLBI Outstanding Investigator Award, and has held leadership roles including Chair of the AHA Western Affiliate Peer Review Committee and Director of the UCSD Stem Cell Program.

Research topics

• Computer Science
• Biology
• Genetics
• Immunology
• Medicine
• Endocrinology
• Cardiology
• Cell biology

Selected publications

• Leptin Receptor Fibroblasts Are Preferential Contributors to Cardiac Fibrosis

  Circulation Research · 2026-04-16 · 1 citations

  articleOpen access

  BACKGROUND: Cardiac fibrosis, a hallmark of heart failure and an unmet clinical need, arises from pathological activation of preexisting cardiac fibroblasts (CFs), but the contribution of CF heterogeneity to this process remains unclear. METHODS: Murine models were used to lineage trace or deplete a specific sub-population of CFs at baseline and after myocardial infarction. Transcriptional and epigenetic differences between fibroblast subsets were assessed using next-generation sequencing. Conservation in humans was evaluated through single-cell RNA-seq data sets and histological examination. RESULTS: In mice, fibroblasts were the sole cardiac cell type expressing the signaling-capable isoform of the LepR (leptin receptor). LepR+ CFs emerged neonatally, occupied a defined niche in the coronary adventitia, exhibited enhanced hedgehog signaling, and responded to leptin. After myocardial infarction, LepR-Cre+ CFs proliferated more than interstitial CFs, became a predominant fibroblast lineage in the scar, and their genetic ablation reduced fibrosis while improving function. LepR+ CFs were also detected in the human heart, where they were embedded in an adipocyte-rich niche. CONCLUSIONS: These findings identify adventitial fibroblasts as key drivers of pathological remodeling and demonstrate that fibroblasts, rather than cardiomyocytes, are the principal responders to leptin in the heart, redefining how this major endocrine pathway influences cardiac remodeling and disease.

  PublisherDOI

• Invasion of Epicardial-Derived Cells to the Trabeculae Mediated by NFPs-Fgf Signaling Regulates Ventricular Compaction

  Circulation Heart Failure · 2026-01-01

  articleOpen access

  BACKGROUND: Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain. METHODS: We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used Tbx18 Cre/+ and inducible WT1 CreERT2/+ to generate epicardium-specific Numb and Numblike double knockouts (epicardial Nb;Nl double knockout [EDKO]) and inducible EpiC-specific Nb;Nl knockout, respectively; monitored EpiCs/EPDCs invasion into the myocardium by lineage tracing; assessed LVNC defects via the ratio of noncompact to compact zone thickness/area; utilized single-nuclei mRNA sequencing and biochemical tools to determine the disrupted molecular mechanisms of EDKOs; and used pharmacological approaches to rescue defects in EDKOs. Cardiac structural and functional changes in adult stages were examined using echocardiography and histochemistry. Sample sizes ranged from 3 to 9 hearts across experiments. RESULTS: Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific Nb;Nl knockouts (induced at embryonic day 10.5) recapitulated the defects. Single-nuclei mRNA sequencing revealed the upregulation of Fgfr1 (fibroblast growth factor receptor 1) in epicardium and the downregulation of Fgf (fibroblast growth factor) ligands in cardiomyocytes in EDKOs. Exogenous Fgf2 supplementation to pregnant females partially rescued epithelial-mesenchymal transition and compaction defects in EDKO hearts. Female EDKOs survived to adulthood and maintained LVNC. CONCLUSIONS: Ablation of NFPs (Numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs–Fgf/Fgfr axis in regulating ventricular compaction.

  PublisherOA PDFDOI

• Transcriptional readthrough at <i>Atf4</i> locus suppresses <i>Rps19bp1</i> and impairs heart development

  Cardiovascular Research · 2025-11-14 · 2 citations

  articleOpen access

  AIMS: Activating transcription factor 4 (ATF4) functions as a transcriptional regulator in various cell types and tissues under both physiological and pathological conditions. While previous studies have linked ATF4 activation with promoting cardiomyocyte (CM) death in dilated cardiomyopathy (DCM), atrial fibrillation, and heart failure, its role in developing CMs remains unexplored. METHODS AND RESULTS: We generated multiple distinct CM-specific (Atf4cKO(e2/3/pA) and Atf4cKO(e2)) and global Atf4 knockout (KO; Atf47del/7del and Atf41ins/1ins) mouse models targeting different Atf4 regions, as well as CM-specific deletion of Rps19bp1 to study cardiac phenotypes. Detailed morphological and molecular analyses were performed. Atf4cKO(e2/3/pA) [targeting exon 2-3 including the polyadenylation signal (polyA)] mice exhibited severe cardiac defects and died before E17.5, likely due to ectopic activation of the p53 signaling pathway resulting from Rps19bp1 downregulation, a potent suppressor of p53. Further investigation revealed that deleting the polyA signal of Atf4 in Atf4cKO(e2/3/pA) mice led to transcriptional readthrough, resulting in the formation of an Atf4-Cacna1i fusion transcript and Rps19bp1 downregulation. To avoid readthrough while abolishing ATF4 function, we introduced small indels into exon 3 of Atf4 in mice (Atf47del/7del and Atf41ins/1ins), which showed normal Rps19bp1 expression and cardiac morphology. Importantly, CM-specific deletion of Rps19bp1 recapitulated the cardiac defects and transcriptional change seen in Atf4cKO(e2/3/pA) mice. CONCLUSION: We found that the downregulation of Rps19bp1, not the loss of ATF4 function, underlies the cardiac phenotypes in Atf4cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 KO models utilizing the Atf4fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models.

  PublisherOA PDFDOI

• Adventitial leptin receptor-expressing fibroblasts are preferential contributors to fibrotic remodeling of the heart post infarction

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-16

  preprintOpen access

  ABSTRACT Background Cardiac fibrosis, a hallmark of heart failure and an unmet clinical need, arises from pathological activation of pre-existing cardiac fibroblasts (CFs), but the contribution of CF heterogeneity to this process remains unclear. Methods Murine models were used to lineage trace or deplete a specific sub-population of CFs at baseline and after myocardial infarction (MI). Transcriptional and epigenetic differences between fibroblast subsets were assessed using next-generation sequencing. Conservation in humans was evaluated through single-cell RNA-seq datasets and histological examination. Results In mice, fibroblasts were the sole cardiac cell type expressing the signaling-capable isoform of the leptin receptor (LepR). LepR+ CFs emerged neonatally, occupied a defined niche in the coronary adventitia, exhibited enhanced hedgehog signaling, and responded to leptin . After MI, LepR-Cre+ CFs proliferated more than interstitial CFs, became a predominant fibroblast lineage in the scar, and their genetic ablation reduced fibrosis while improving function. LepR+ CFs were also detected in the human heart, where they were embedded in an adipocyte-rich niche. Conclusions These findings identify adventitial fibroblasts as key drivers of pathological remodeling and demonstrate that fibroblasts, rather than cardiomyocytes, are the principal responders to leptin in the heart, redefining how this major endocrine pathway influences cardiac remodeling and disease.

  PublisherOA PDFDOI

• The Islet-1 Interaction Partner Rnf20 Regulates Glucose Homeostasis and Pancreatic β-cell Identity

  2025-07-31

  preprintOpen access

  &lt;p dir="ltr"&gt;Diabetes is characterized by a loss of functional β-cell mass, therefore identifying factors involved in establishing and preserving β-cells is critical to combat rising diabetes incidence. While transcription factors are crucial β-cell regulators, knowledge of co-regulators facilitating gene expression is limited. Previously, we demonstrated that the Islet-1 transcription factor forms complexes with ubiquitin ligases Rnf20 and Rnf40 to regulate β-cells &lt;i&gt;in vitro&lt;/i&gt;. Here, we investigate whether Rnf20-mediated complexes are required for β-cell function in adult islets by characterizing a novel β-cell-enriched &lt;i&gt;Rnf20&lt;/i&gt; knockout mouse model. Tamoxifen induction of &lt;i&gt;Rnf20&lt;/i&gt; recombination prompts a robust loss of histone 2B monoubiquitination (H2Bub1), imparts severe hyperglycemia, glucose intolerance, and elicits an overall reduction in insulin content. Expression of mRNAs and proteins involved in glucose stimulated insulin secretion and β-cell identity are also dysregulated in &lt;i&gt;Rnf20&lt;/i&gt;&lt;sup&gt;&lt;em&gt;Δβ-cell&lt;/em&gt;&lt;/sup&gt; mice. Comparative analyses of the loss of either &lt;i&gt;Rnf20&lt;/i&gt; or &lt;i&gt;Isl1 &lt;/i&gt;yields similar changes in the β-cell regulome, supporting that Isl1::Rnf20 complexes are critical regulators of β-cell identity and function. Isl1::Rnf20 complexes are maintained in human tissues wherein they regulate insulin expression, secretion, and content. These findings increase our understanding of key players in β-cell maintenance, which is crucial for the advancement of β-cell derivation diabetes therapeutics.&lt;/p&gt;

  PublisherDOI

• Transcriptional Readthrough at <i>Atf4</i> Locus Suppresses <i>Rps19bp1</i> and Impairs Heart Development

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-29

  preprintOpen access

  BACKGROUND Activating Transcription Factor 4 (ATF4) functions as a transcriptional regulator in various cell types and tissues under both physiological and pathological conditions. While previous studies have linked ATF4 activation with promoting cardiomyocyte (CM) death in dilated cardiomyopathy (DCM), atrial fibrillation, and heart failure, its role in developing CMs remains unexplored. METHODS We generated multiple distinct CM-specific ( Atf4 cKO(e2/3/pA) and Atf4 cKO(e2) ) and global Atf4 knockout ( Atf4 7del/7del and Atf4 1ins/1ins ) mouse models targeting different Atf4 regions, as well as cardiomyocyte-specific deletion of Rps19bp1 to study cardiac phenotypes. Detailed morphological and molecular analyses were performed. RESULTS Atf4 cKO( e2/3 /pA) (targeting exon 2-3 including the polyadenylation signal (polyA)) mice exhibited severe cardiac defects and died before E17.5, likely due to ectopic activation of p53 signaling pathway resulting from Rps19bp1 downregulation, a potent suppressor of p53. Further investigation revealed that deleting the polyA signal of Atf4 in Atf4 cKO(e2/3/pA) mice led to transcriptional readthrough, resulting in the formation of an Atf4 - Cacna1i fusion transcript and Rps19bp1 downregulation. To avoid readthrough while abolishing ATF4 function, we introduced small indels into exon 3 of Atf4 in mice ( Atf4 7del/7del and Atf4 1ins/1ins ), which showed normal Rps19bp1 expression and cardiac morphology. Importantly, CM-specific deletion of Rps19bp1 recapitulated the cardiac defects and transcriptional change seen in Atf4 cKO(e 2 /3/pA) mice. CONCLUSIONS We found that the downregulation of Rps19bp1 , not loss of ATF4 function, underlying the cardiac phenotypes in Atf4 cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4 cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 knockout models utilizing the Atf4 fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models. TRANSLATIONAL PERSPECTIVE Our findings clarify ATF4’s role in heart development by showing that cardiac defects in cardiomyocyte-specific ATF4 knockout mice—using a widely employed floxed ATF4 line—result from unintended downregulation of RPS19BP1 caused by transcriptional readthrough. This shifts the focus from ATF4 to RPS19BP1, a key regulator of p53 activity, as a potential driver of cardiac developmental abnormalities. Clinically, these insights caution against misinterpretation of genetic knockout models and highlight RPS19BP1 as a promising target for congenital heart disease and related cardiac dysfunctions, with potential implications for future therapies.

  PublisherOA PDFDOI

• Ets1-regulated endothelial-secreted factors promote compact myocardial growth and contribute to the pathogenesis of ventricular non-compaction

  Cardiovascular Research · 2025-12-02 · 1 citations

  articleOpen access

  AIMS: Thinning of the compact myocardium is a major contributor to adverse outcomes in ventricular non-compaction, the third most common form of cardiomyopathy. Endothelial-specific deletion of Ets1, a gene associated with Jacobsen syndrome, causes ventricular non-compaction with reduced compact myocardium. However, the mechanisms by which pathological cardiac endothelium impairs compact myocardium growth remain poorly understood. METHODS AND RESULTS: To uncover the mechanisms underlying compact myocardium thinning and identify therapeutic endothelial-secreted factors, we performed single-cell RNA sequencing. Aberrant cardiomyocyte and endothelial cell states were observed in non-compacted ventricles. Conditional deletion of Ets1 in either the endocardium or coronary endothelium impaired compact myocardial growth. In endocardium, Ets1 deficiency suppressed Notch1 signaling by upregulating Dlk1 and downregulating Dll4, both direct Ets1 targets. In coronary endothelium, Ets1 deficiency reduced the expression of its direct targets Hmcn1, Slit2, and Col18a1, three extracellular matrix (ECM) components that promote compact myocardial proliferation. Notably, treatment with these ECM proteins or the Notch1 effector Nrg1 restored the impaired compact myocardial proliferation. CONCLUSION: These findings highlight Ets1-regulated endothelial-secreted factors as essential for compact myocardium development and suggest novel therapeutic targets for ventricular non-compaction.

  PublisherOA PDFDOI

• Tunneling nanotube–like structures regulate distant cellular interactions during heart formation

  Science · 2025-03-13 · 19 citations

  articleOpen access

  In the developing mammalian heart, the endocardium and the myocardium are separated by so-called cardiac jelly. Communication between the endocardium and the myocardium is essential for cardiac morphogenesis. How membrane-localized receptors and ligands achieve interaction across the cardiac jelly is not understood. Working in developing mouse cardiac morphogenesis models, we used a variety of cellular, imaging, and genetic approaches to elucidate this question. We found that myocardium and endocardium interacted directly through microstructures termed tunneling nanotube-like structures (TNTLs). TNTLs extended from cardiomyocytes (CMs) to contact endocardial cells (ECs) directly. TNTLs transported cytoplasmic proteins, transduced signals between CMs and ECs, and initiated myocardial growth toward the heart lumen to form ventricular trabeculae-like structures. Loss of TNTLs disturbed signaling interactions and, subsequently, ventricular patterning.

  PublisherOA PDFDOI

• eLife Assessment: A cell atlas of the developing human outflow tract of the heart and its adult derivatives

  2025-09-11

  peer-reviewOpen access1st authorCorresponding

  The outflow tract (OFT) of the heart carries blood away from the heart into the great arteries. During embryogenesis, the OFT divides to form the aorta and pulmonary trunk, creating the double circulation present in mammals. Defects in this area account for one-third of all congenital heart disease cases. Here, we present comprehensive transcriptomic data on the developing OFT at two distinct timepoints (embryonic and fetal) and its adult derivatives, the aortic valves, and use spatial transcriptomics to define the distribution of cell populations. We uncover that distinctive embryonic signatures persist in adult cells and can be used as labels to retrospectively attribute relationships between cells separated by a large time scale. Single- cell regulatory network inference identifies GATA6, a transcription factor linked to common arterial trunk and bicuspid aortic valve, as a key regulator of valve precursor cells. Its downstream network reveals candidate drivers of human cardiac defects and illuminates the molecular mechanisms of both normal and pathological valve development. Our findings define the cellular and molecular signatures of the human OFT and its distinct cell lineages, which is critical for understanding congenital heart defects and developing cardiac tissue for regenerative medicine.

  PublisherDOI

• The Islet-1 Interaction Partner Rnf20 Regulates Glucose Homeostasis and Pancreatic β-Cell Identity

  Diabetes · 2025-07-31

  articleOpen access

  Diabetes is characterized by a loss of functional β-cell mass; therefore, identifying factors involved in establishing and preserving β-cells is critical to combat rising diabetes incidence. While transcription factors are crucial β-cell regulators, knowledge of coregulators facilitating gene expression is limited. Previously, we demonstrated that the islet-1 (Isl1) transcription factor forms complexes with ubiquitin ligases ring finger 20 (Rnf20) and Rnf40 to regulate β-cells in vitro. Here, we investigated whether Rnf20-mediated complexes are required for β-cell function in adult islets by characterizing a novel β-cell-enriched Rnf20 knockout mouse model. Tamoxifen induction of Rnf20 recombination prompted a robust loss of histone 2B monoubiquitination, imparted severe hyperglycemia and glucose intolerance, and elicited an overall reduction in insulin content. Expression of mRNAs and proteins involved in glucose-stimulated insulin secretion and β-cell identity were also dysregulated in Rnf20Δβ-cell mice. Comparative analyses of the loss of either Rnf20 or Isl1 yielded similar changes in the β-cell regulome, supporting that Isl1::Rnf20 complexes are critical regulators of β-cell identity and function. Isl1::Rnf20 complexes are maintained in human tissues wherein they regulate insulin expression, secretion, and content. These findings increase our understanding of key players in β-cell maintenance, which is crucial for the advancement of β-cell derivation diabetes therapeutics. ARTICLE HIGHLIGHTS: Transcription factor Islet-1 (Isl1) and ubiquitin ligase Ring Finger 20 (Rnf20) complexes regulate insulin secretion and β-cell gene expression in vitro. Loss of Rnf20 in adult β-cells disrupts β-cell identity and insulin processing, production, and secretion. In complex with Isl1, Rnf20 influences the β-cell regulome and supports proper glucose homeostasis.

  PublisherOA PDFDOI

Recent grants

• Endocardial Pathways Regulated by Tbx20

  NIH · $2.2M · 2013–2018

• NIH Grant R29HL046761

  NIH · $527k · 1997

• The Role of Dot1L in developing and postnatal heart

  NIH · $1.5M · 2014–2019

• NIH Grant R01HL070867

  NIH · $3.1M · 2011

• Renewing the heart: cardiomyocyte cell cycle regulation

  NIH · $6.1M · 2019–2026

Frequent coauthors

• Ju Chen

  Xi'an University of Technology

  119 shared

• Nuno Guimarães‐Camboa

  Goethe University Frankfurt

  80 shared

• Lucie Carrier

  Universität Hamburg

  80 shared

• Paola Cattaneo

  74 shared

• Felix W. Friedrich

  68 shared

• Thomas Eschenhagen

  Universität Hamburg

  68 shared

• Thomas Moore‐Morris

  Institut de Génomique Fonctionnelle

  67 shared

• Yusu Gu

  University of California, San Diego

  67 shared

Awards & honors

• Muscular Dystrophy Association Fellowship (1986-1988)
• Schulman Prize in Cardiovascular Research at UCSD (1998,1999…
• Lethbridge Collegiate Institute: Distinguished Graduate Awar…
• Invited participant in NIH Workshop to Determine Future Dire…
• Member of American Heart Association Reclassification Task F…