About

Professor Frank Conlon is affiliated with the Department of Genetics at the University of North Carolina at Chapel Hill. His research focuses on identifying the molecular networks essential for early heart development and investigating how sex differences in these networks contribute to sex disparities in heart disease. His lab employs an integrated approach that combines developmental, genetic, proteomic, biochemical, and molecular studies using mouse models and stem cells to advance understanding in this area.

Research topics

• Biology
• Genetics
• Statistics
• Endocrinology
• Internal medicine
• Physiology
• Computational biology

Selected publications

• DDX3X-mediated translation of structured cardiac mRNAs is essential for female heart development

  Genes & Development · 2026-04-27

  preprintOpen accessSenior author

  Sex differences influence congenital heart disease (CHD) development, yet underlying molecular mechanisms remain largely unclear. We demonstrate that the X-linked RNA helicase DDX3X associates in the heart with ribosomal subunit proteins, and eCLIP mapping reveals its preferential binding to cardiac mRNAs with long, structured 5′ untranslated regions (UTRs) that can hinder translation. Using a cardiomyocyte-specific mouse Ddx3x knockout model, we show that female embryos lacking Ddx3x die at midgestation from heart failure due to impaired translation of key cardiac regulators, whereas male littermates survive. Ribosome profiling and proteomics demonstrate that DDX3X is required for efficient translation of female differential cardiac mRNAs. Reporter assays confirm that translation of essential cardiac genes such as Srf and Rcor2 depends on their 5′ UTRs and requires DDX3X. These findings uncover a sex-specific posttranscriptional mechanism by which DDX3X safeguards female heart development through selective mRNA translation, providing insight into how X-linked dosage-sensitive regulators contribute to CHD.

  PublisherDOI

• TBX5 and CHD4 Coordinately Activate Atrial Cardiomyocyte Genes to Maintain Cardiac Rhythm Homeostasis.

  UNC Libraries · 2026-04-25

  articleOpen access

  BACKGROUND: Atrial fibrillation, the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 (T-box 5) is essential for normal atrial rhythm. Its inactivation causes loss of atrial cardiomyocyte (aCM) enhancer accessibility, looping, transcriptional identity, and spontaneous atrial fibrillation. TBX5 interacts with CHD4 (chromodomain helicase DNA-binding protein 4), a chromatin remodeling ATPase canonically associated with the NuRD (nucleosome remodeling and deacetylase) repressor complex. METHODS: We investigated mechanisms by which TBX5 regulates chromatin organization by studying mice with aCM-selective inactivation of TBX5 or CHD4. We integrated multiple genomics approaches including concurrent single-nucleus transcriptome and open chromatin profiling and genome-wide TBX5 and CHD4 chromatin occupancy assays. RESULTS: We found that TBX5 recruits CHD4 to 33&thinsp;170 genomic regions (TBX5-enhanced CHD4 sites). In addition to the canonical repressive activity of CHD4, we uncovered a CHD4 activator function predominantly at sites to which it was recruited by TBX5. TBX5-enhanced CHD4 recruitment increased local chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of CHD4 recruitment by TBX5 was crucial for sinus rhythm; mice with CHD4 inactivation in aCMs had increased atrial fibrillation vulnerability. Assaying TBX5 binding in <em>Chd4</em>^<em>AKO</em> atria demonstrated that CHD4 also promotes TBX5 binding at &gt;10&thinsp;000 genomic loci, including 3051 TBX5-enhanced CHD4 sites. Consistent with its requirement to maintain normal atrial rhythm, CHD4 was implicated in the regulation of 42 genes linked to atrial fibrillation in humans. Nine had the hallmarks of TBX5-dependent, CHD4-mediated transcriptional activation. CONCLUSIONS: Our findings reveal that normal atrial rhythm requires CHD4, which activates and represses atrial genes in a context-dependent manner to maintain aCM gene expression, aCM identity, and atrial rhythm homeostasis.

  PublisherDOI

• Quantitative proteomic profiling identifies global protein network dynamics in murine embryonic heart development

  UNC Libraries · 2025-07-26

  articleOpen access
  PublisherDOI

• The Interplay of Ontogeny and Phylogeny at the Transcriptome Level of the Tetrapod Heart

  UNC Libraries · 2025-07-25

  articleOpen access1st authorCorresponding

  The tetrapod heart is characterized by three chambers in amphibians and non-avian reptiles, as opposed to four in birds, crocodilians and mammals. We explored this diversity via the most phylogenetically comprehensive comparison of heart transcriptomes undertaken to date. Transcriptomes representing the ontogeny of heart compartmentalization (septation) in alligator, chicken, frog, mouse, lizard and turtle embryos exhibited a clear species-specific signal, which was driven by genes involved in heart contraction. During the stage dominated by septation-related tissue transformations, the most highly expressed genes shared by species originated before the tetrapods diversified and were related to septum morphogenesis, ventricular development, and chamber formation. The expression of septation-related genes did not adhere to phylogeny or heart chamber number, and genes differentially expressed across developmental stages within species varied in their evolutionary ages and predicted functions. We discuss how the acquisition of novel structures in some lineages, convergent evolution of four heart chambers, embryonic metabolism, microstructural variation, and ontogenetic shifts (heterochronies), collectively, provide insight into evolved and conserved patterns of transcriptome-level variation. These data serve as a resource to further stimulate evo-devo research on complex organ systems, such as the heart.

  PublisherDOI

• Sex-specific response to A1BG loss results in female dilated cardiomyopathy

  Biology of Sex Differences · 2025-04-23

  articleOpen accessSenior author

  BACKGROUND: Cardiac disease often manifests with sex-specific differences in frequency, pathology, and progression. However, the molecular mechanisms underlying these differences remain incompletely understood. The glycoprotein A1BG has emerged as a female-specific regulator of cardiac structure and integrity, yet its precise role in the female heart is not well characterized. METHODS: To investigate the sex-specific role of A1BG in the heart, we generated both a conditional A1bg knockout allele and an A1bg Rosa26 knockin allele. We employed histological analysis, electrocardiography, RNA sequencing (RNA-seq), transmission electron microscopy (TEM), western blotting, mass spectrometry, and immunohistochemistry to assess structural, functional, and molecular phenotypes. RESULTS: mice left ventricular dilation and wall thinning are evident and sustained over time, consistent with early-stage dilated cardiomyopathy (DCM). Transcriptomic analyses reveal that A1BG regulates key metabolic pathways in females, including glucose-6-phosphate and acetyl-CoA metabolism. TEM imaging highlights sex-specific disruption of intercalated disc architecture in female cardiomyocytes. These findings suggest that the absence of A1BG initiates chronic pathological remodeling in female hearts, potentially predisposing them to DCM under stress or aging. CONCLUSION: A1BG is essential for maintaining ventricular structural integrity in female, but not male, hearts, leading to a chronic remodeling consistent with early-stage DCM.

  PublisherOA PDFDOI

• X-Chromosome–Linked miRNAs Regulate Sex Differences in Cardiac Physiology

  UNC Libraries · 2025-07-01

  articleOpen access1st authorCorresponding

  BACKGROUND: Males and females exhibit distinct anatomic and functional characteristics of the heart, predisposing them to specific disease states. METHODS: We identified microRNA (miRNAs/miR) with sex-differential expression in mouse hearts. RESULTS: Four conserved miRNAs are present in a single locus on the X-chromosome and are expressed at higher levels in females than males. We show miRNA, miR-871, is responsible for decreased expression of the protein SRL (sarcalumenin) in females. SRL is involved in calcium signaling, and we show it contributes to differences in electrophysiology between males and females. miR-871 overexpression mimics the effects of the cardiac physiology of conditional cardiomyocyte-specific Srl-null mice. Inhibiting miR-871 with an antagomir in females shortened ventricular repolarization. The human orthologue of miR-871, miR-888, coevolved with the SRL 3&prime; untranslated region and regulates human SRL. CONCLUSIONS: These data highlight the importance of sex-differential miRNA mechanisms in mediating sex-specific functions and their potential relevance to human cardiac diseases.

  PublisherDOI

• TBX5 and CHD4 Coordinately Activate Atrial Cardiomyocyte Genes to Maintain Cardiac Rhythm Homeostasis

  Circulation · 2025-08-13 · 4 citations

  articleOpen access

  BACKGROUND: Atrial fibrillation, the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 (T-box 5) is essential for normal atrial rhythm. Its inactivation causes loss of atrial cardiomyocyte (aCM) enhancer accessibility, looping, transcriptional identity, and spontaneous atrial fibrillation. TBX5 interacts with CHD4 (chromodomain helicase DNA-binding protein 4), a chromatin remodeling ATPase canonically associated with the NuRD (nucleosome remodeling and deacetylase) repressor complex. METHODS: We investigated mechanisms by which TBX5 regulates chromatin organization by studying mice with aCM-selective inactivation of TBX5 or CHD4. We integrated multiple genomics approaches including concurrent single-nucleus transcriptome and open chromatin profiling and genome-wide TBX5 and CHD4 chromatin occupancy assays. RESULTS: We found that TBX5 recruits CHD4 to 33 170 genomic regions (TBX5-enhanced CHD4 sites). In addition to the canonical repressive activity of CHD4, we uncovered a CHD4 activator function predominantly at sites to which it was recruited by TBX5. TBX5-enhanced CHD4 recruitment increased local chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of CHD4 recruitment by TBX5 was crucial for sinus rhythm; mice with CHD4 inactivation in aCMs had increased atrial fibrillation vulnerability. Assaying TBX5 binding in Chd4 AKO atria demonstrated that CHD4 also promotes TBX5 binding at &gt;10 000 genomic loci, including 3051 TBX5-enhanced CHD4 sites. Consistent with its requirement to maintain normal atrial rhythm, CHD4 was implicated in the regulation of 42 genes linked to atrial fibrillation in humans. Nine had the hallmarks of TBX5-dependent, CHD4-mediated transcriptional activation. CONCLUSIONS: Our findings reveal that normal atrial rhythm requires CHD4, which activates and represses atrial genes in a context-dependent manner to maintain aCM gene expression, aCM identity, and atrial rhythm homeostasis.

  PublisherOA PDFDOI

• Abstract Thu165: X-linked Demethylase KDM6A is Differentially Required in Male and Female Hearts

  Circulation Research · 2025-08-01

  articleSenior author

  Background: Sex differences are prevalent across many human diseases, including both adult and congenital cardiovascular disease. Uncovering the mechanisms driving these sex differences is necessary to advance clinical approaches for both men and women with heart disease. KDM6A (formally UTX) is an X-chromosome-linked H3K27 demethylase that specifically removes histone H3 lysine K27 trimethylation, thereby priming transcriptional activation. Mutations in KDM6A cause Kabuki syndrome in humans, a rare congenital craniofacial disorder commonly associated with heart defects. Studies in mice have shown that Kdm6a is critical for embryonic stem cell differentiation into cardiomyocytes (CMs) and global homozygous deletion of Kdm6a leads to embryonic lethality in female, but not male, mice due to developmental heart defects. While there is substantial evidence that KDM6A plays a critical role in the heart, the sex-specific epigenetic function of KDM6A within the heart remains unknown. Methods: We have employed a CM-specific KDM6A conditional null mouse model ( Kdm6a cmKO) to determine the sex-specific requirement for KDM6A in male and female hearts. Results: We find that KDM6A loss in CMs during heart development has sex-specific effects on cardiac conduction in adult mice. We also report widespread gene dysregulation in distinct pathways in male and female adult Kdm6a cmKO CMs, including opposing effects on genes involved in contractility, ion transport, and calcium ion homeostasis. Finally, we find that postnatal KDM6A loss exclusively impacts cardiac conduction in female mice and results in distinct electrocardiogram signatures compared to female Kdm6a cmKO mice. Discussion: Ongoing work aims to identify the sex-specific genomic targets of KDM6A at key developmental and postnatal time points. Overall, this research will define a sex-specific role for KDM6A in the epigenetic regulation of gene expression within the heart and will provide further insight into the biological mechanisms underlying sex differences in human heart physiology and disease.

  PublisherDOI

• Sex-chromosome mechanisms in cardiac development and disease

  UNC Libraries · 2025-07-25

  articleOpen accessSenior author
  PublisherDOI

• The Interplay of Ontogeny and Phylogeny at the Transcriptome Level of the Tetrapod Heart

  Journal of Experimental Zoology Part B Molecular and Developmental Evolution · 2025-07-03 · 1 citations

  articleOpen access

  The tetrapod heart is characterized by three chambers in amphibians and non-avian reptiles, as opposed to four in birds, crocodilians and mammals. We explored this diversity via the most phylogenetically comprehensive comparison of heart transcriptomes undertaken to date. Transcriptomes representing the ontogeny of heart compartmentalization (septation) in alligator, chicken, frog, mouse, lizard and turtle embryos exhibited a clear species-specific signal, which was driven by genes involved in heart contraction. During the stage dominated by septation-related tissue transformations, the most highly expressed genes shared by species originated before the tetrapods diversified and were related to septum morphogenesis, ventricular development, and chamber formation. The expression of septation-related genes did not adhere to phylogeny or heart chamber number, and genes differentially expressed across developmental stages within species varied in their evolutionary ages and predicted functions. We discuss how the acquisition of novel structures in some lineages, convergent evolution of four heart chambers, embryonic metabolism, microstructural variation, and ontogenetic shifts (heterochronies), collectively, provide insight into evolved and conserved patterns of transcriptome-level variation. These data serve as a resource to further stimulate evo-devo research on complex organ systems, such as the heart.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HL075256

  NIH · $1.3M · 2007

• Gene Regulatory Networks for Cardiac Morphogenesis

  NIH · $2.5M · 2017–2021

• Cardiac interaction networks as determinants of transcriptional specificity

  NIH · $2.9M · 2017–2023

• NIH Grant R01HL127640

  NIH · $2.5M · 2020

• NIH Grant R01HL089641

  NIH · $1.5M · 2012

Frequent coauthors

• Ileana M. Cristea

  Princeton University

  29 shared

• Todd M. Greco

  24 shared

• Panna Tandon

  Edinburgh College

  23 shared

• Deborah Yelon

  University of California, San Diego

  21 shared

• Nirav M. Amin

  Digital Science (United States)

  19 shared

• Margaret L. Kirby

  18 shared

• Sylvia Μ. Evans

  University of California, San Diego

  18 shared

• Kerry M. Dorr

  University of North Carolina at Chapel Hill

  18 shared

Education

• Ph.D., Genetics & Development

  Columbia University