Biology subjects

Yucel, D.

Publications and source records attributed to Yucel, D..

5 recordsLinked to original sources

bioRxiv2025

Mechanisms of Cardiomyocyte Aging

Aging is a major risk factor for cardiovascular diseases, yet the underlying molecular mechanisms remain poorly understood. In this study, we integrated physiological characterization of cardiomyocyte (CM) aging with concurrent single-nucleus RNA-seq and ATAC-seq, and reduced representation bisulfite sequencing to delineate the cellular and molecular landscape of CM aging in mice. Our analysis revealed significant age-associated changes in CM physiology, including hypertrophy, fibrosis, and diastolic dysfunction. We uncovered dramatic epigenetic remodeling in aged CMs, characterized by increased chromatin accessibility and altered DNA methylation patterns. Overexpression of the DNA methylase DNMT3A in young adult mouse hearts recapitulated key features of the aged heart phenotype, establishing DNA hypermethylation as a significant regulator of age-related CM function. Furthermore, ESRRG, an orphan nuclear receptor, functions as a mediator of diastolic function in the heart. Its overexpression significantly improved diastolic function and reduced expression of a non-coding RNA that is upregulated in aged CMs. These novel insights into the molecular mechanisms underlying cardiac aging identify molecular regulators involved in age-associated cardiac remodeling.

molecular biology↗

bioRxiv2024

Myocardial Endoglin Regulates Cardiomyocyte Proliferation and Cardiac Regeneration

The mammalian heart loses almost all its regenerative potential in the first week of life due to the cessation of the ability of cardiomyocytes to proliferate. In recent years, a number of regulators of cardiomyocyte proliferation have been identified. Despite this, a clear understanding of the regulatory pathways that control cardiomyocyte proliferation and cardiac regeneration is lacking, and there are likely additional regulators to be discovered. Here, we performed a genome-wide screen on fetal murine cardiomyocytes to identify potential novel regulators of cardiomyocyte proliferation. Endoglin was identified as an inhibitor of cardiomyocyte proliferation in vitro. Endoglin knock-down resulted in enhanced DNA synthesis, cardiomyocyte mitosis and cytokinesis in mouse, rat and human cardiomyocytes. Using gene-targeted mice, we confirmed myocardial Endoglin to be important in cardiomyocyte proliferation and cardiac regeneration using gene-targeted mice. Mechanistically, we show that Smad signaling is required for the endoglin-mediated anti-proliferative effects. Our results identify the TGF-{beta} coreceptor Endoglin as a regulator of cardiac regeneration and cardiomyocyte proliferation. SummaryHigh-content function screening is used to identify a novel inhibitor of cardiomyocyte proliferation which can promote mammalian cardiac regeneration.

genetics↗

bioRxiv2024

Macrophage-derived CCL24 promotes fibrosis and worsens cardiac dysfunction during heart failure

Inflammation is a significant risk factor and contributes to cardiovascular disease by driving both adaptive and maladaptive processes. Macrophages are the most abundant immune cells in the heart and play an important role in the remodeling of cardiac tissue. We have previously shown an overall protective function of resident cardiac macrophages after pressure-overloaded injury. However, a subpopulation of resident macrophages also expresses high levels of the profibrotic CC motif chemokine ligand 24 (CCL24), suggesting a dichotomous role in pressure overload-induced cardiac remodeling. Here, we report that following transverse aortic constriction CCL24 knockout (CCL24 KO) mice have improved systolic function, cardiac wall enlargement, as well as increased myocyte surface area and hypertrophy, suggesting that CCL24 disrupts compensatory hypertrophy. TAC-operated CCL24 KO mice also displayed reduced fibrosis and diminished expression of fibrotic genes, implying a pro-fibrotic role for CCL24. Indeed, CCL24 induced the proliferation and activation of primary mouse fibroblasts in a process that required CCR3, the sole G protein-coupled receptor for CCL24. Correspondingly, selective ablation of CCR3 in fibroblasts improved cardiac function and ameliorated fibrosis following pressure overload. Administration of a CCL24 blocking antibody or a CCR3 antagonist both improved cardiac function in pressure-overloaded mice, highlighting the CCL24-CCR3 axis as a potential therapeutic target for heart failure. Finally, CCL24 deficiency improved cardiac function and ameliorated fibrosis during physiological aging. Overall, these results show that macrophage-derived CCL24 aggravates fibrosis via the CCR3 receptor, leading to impaired cardiac function in acute and chronic heart failure.

immunology↗

bioRxiv2020

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Meis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This led us to develop inhibitors of MEIS1 that could modulate HSC activity. To this end, we have established a library of relevant homeobox family inhibitors and developed a high-throughput in silico screening strategy against homeodomain of MEIS proteins using the AutoDock Vina and PaDEL-ADV platform. We have screened over a million druggable small molecules in silico and selected putative MEIS inhibitors (MEISi) with no predicted cytotoxicity or cardiotoxicity. This was followed by in vitro validation of putative MEIS inhibitors using MEIS dependent luciferase reporter assays and analysis in the ex vivo HSC assays. We have shown that small molecules named MEISi-1 and MEISi-2 significantly inhibit MEIS-luciferase reporters in vitro and induce murine (LSKCD34low cells) and human (CD34+, CD133+, and ALDHhi cells) HSC self-renewal ex vivo. In addition, inhibition of MEIS proteins results in downregulation of Meis1 and MEIS1 target gene expression including Hif-1, Hif-2 and HSC quiescence modulators. MEIS inhibitors are effective in vivo as evident by induced HSC content in the murine bone marrow and downregulation of expression of MEIS target genes. These studies warrant identification of first-in-class MEIS inhibitors as potential pharmaceuticals to be utilized in modulation of HSC activity and bone marrow transplantation studies.

molecular biology↗

bioRxiv2018

c-Myc inhibition is critical for HSC expansion and Rad51 expression

c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence. Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion. Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34low HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclin-dependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo. In addition, c-Myc inhibition upregulates major HDR modulator Rad51 expression in hematopoietic cells. Besides, c-Myc inhibition does not alter proliferation kinetics of endothelial cells, fibroblasts or adipose derived mesenchymal stem cells, however; it limits bone marrow derived mesenchymal stem cell proliferation. We further demonstrate that a cocktail of c-Myc inhibitor 10074-G5 along with tauroursodeoxycholic acid (TUDCA) and i-NOS inhibitor L-NIL provides a robust HSC maintenance and expansion ex vivo as evident by induction of all stem cell antigens analyzed. Intriguingly, the cocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL improves HDR related gene expression. These findings provide tools to improve ex vivo HSC maintenance and expansion, autologous HSC transplantation and gene editing through modulation of HSC glycolytic and HDR pathways.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC=\"FIGDIR/small/403584_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (65K):\norg.highwire.dtl.DTLVardef@a34597org.highwire.dtl.DTLVardef@12dcc37org.highwire.dtl.DTLVardef@1ba68edorg.highwire.dtl.DTLVardef@13edbfd_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG HighlightsO_LIc-Myc inhibition induces ex vivo murine and human hematopoietic stem and progenitor cell proliferation and in vivo murine HSC pool\nC_LIO_LIc-Myc inhibition downregulates CDKIs and glycolytic gene expression in hematopoietic cells\nC_LIO_LIc-Myc inhibition do not cause apparent changes to endothelial cells, fibroblasts, or AD-MSCs but it limits BM-MSC proliferation\nC_LIO_LIc-Myc inhibition along with TUDCA and L-NIL improves HSC maintenance and expansion as evident by induction of all HSC surface antigens analyzed\nC_LIO_LIc-Myc inhibition alone upregulates major HDR modulator Rad51 expression in hematopoietic cells\nC_LIO_LICocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL improves HDR and S-phase related gene expression\nC_LI

cell biology↗