Biology subjects

DeLuca, S.

Publications and source records attributed to DeLuca, S..

4 recordsLinked to original sources

bioRxiv2025

Organ-specific rewiring of mitochondrial integrity through COX7A dictates cellular ploidy control

To achieve proper cell and tissue size, cytoplasmic and nuclear growth must be coordinated. Disrupting this coordination causes birth defects and disease. In natures largest cells, nuclear growth occurs through polyploidization (whole-genome-duplication). How the massive nuclear growth of polyploid cells is coordinated with cytoplasmic growth processes such as mitochondrial biogenesis is relatively unclear. Here, focusing on one of natures most commonly polyploid organs-the heart-we uncover cross-talk between cytoplasmic mitochondrial biogenesis/integrity and nuclear growth/polyploidy. From a human-to-fly screen, we uncover novel regulators of cardiomyocyte ploidy, including mitochondrial integrity regulators. In comparing these cardiac hits with a parallel screen in another polyploid tissue, the salivary gland, we discovered two opposing roles for Cytochrome-c-oxidase-subunit-7A (COX7A). While salivary gland COX7A preserves mitochondrial integrity to promote polyploidy and optimal organ growth, cardiac COX7A instead suppresses mitochondrial biogenesis to repress polyploidy and prevent hypertrophic organ growth. Among all electron transport chain genes, only COX7A functions as a cardiac growth repressor. Fly hearts with compromised COX7A show abnormally high cardiac output. Human COX7A1, a mitochondrial-localized protein, similarly represses polyploidy of human iPSC-derived cardiomyocytes. In summary, our human-fly-human approach reveals conserved rewiring of mitochondrial integrity in heart tissue that switches COX7As role from ploidy promotion to repression. Our findings reveal fundamental cross-talk between mitochondrial biogenesis and genome duplication that are critical in growing metazoan tissues.

developmental biology↗

bioRxiv2024

Blended Genome Exome (BGE) as a Cost Efficient Alternative to Deep Whole Genomes or Arrays

Genomic scientists have long been promised cheaper DNA sequencing, but deep whole genomes are still costly, especially when considered for large cohorts in population-level studies. More affordable options include microarrays + imputation, whole exome sequencing (WES), or low-pass whole genome sequencing (WGS) + imputation. WES + array + imputation has recently been shown to yield 99% of association signals detected by WGS. However, a method free from ascertainment biases of arrays or the need for merging different data types that still benefits from deeper exome coverage to enhance novel coding variant detection does not exist. We developed a new, combined, "Blended Genome Exome" (BGE) in which a whole genome library is generated, an aliquot of that genome is amplified by PCR, the exome regions are selected and enriched, and the genome and exome libraries are combined back into a single tube for sequencing (33% exome, 67% genome). This creates a single CRAM with a low-coverage whole genome (2-3x) combined with a higher coverage exome (30-40x). This BGE can be used for imputing common variants throughout the genome as well as for calling rare coding variants. We tested this new method and observed >99% r2 concordance between imputed BGE data and existing 30x WGS data for exome and genome variants. BGE can serve as a useful and cost-efficient alternative sequencing product for genomic researchers, requiring ten-fold less sequencing compared to 30x WGS without the need for complicated harmonization of array and sequencing data.

genomics↗

bioRxiv2023

Chromatin and gene expression changes during female Drosophila germline stem cell development illuminate the biology of highly potent stem cells

Highly potent animal stem cells either self renew or launch complex differentiation programs, using mechanisms that are only partly understood. Drosophila female germline stem cells (GSC) perpetuate without change over evolutionary time and generate cystoblast daughters that develop into nurse cells and oocytes. Cystoblasts initiate differentiation by generating a transient syncytial state, the germline cyst, and by increasing pericentromeric H3K9me3 modification, actions likely to suppress transposable element activity. Relatively open GSC chromatin is further restricted by Polycomb repression of testis or somatic cell-expressed genes briefly active in early female germ cells. Subsequently, Neijre/CBP and Myc help upregulate growth and reprogram GSC metabolism by altering mitochondrial transmembrane transport, gluconeogenesis and other processes. In all these respects GSC differentiation resembles development of the totipotent zygote. We propose that the totipotent stem cell state was shaped by the need to resist transposon activity over evolutionary time scales.

developmental biology↗

bioRxiv2020

Human Erbb2-induced Erk Activity Robustly Stimulates Cycling and Functional Remodeling of Rat and Human Cardiomyocytes

Multiple mitogenic pathways capable of promoting mammalian cardiomyocyte (CM) proliferation have been identified as potential candidates for functional heart repair following myocardial infarction. However, it is unclear whether the effects of these mitogens are species-specific and how they directly compare in the same cardiac setting. Here, we examined how CM-specific lentiviral expression of various candidate mitogens affects human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) in vitro. In 2D-cultured CMs from both species, and in highly mature 3D-engineered cardiac tissues generated from NRVMs, a constitutively-active mutant form of the human gene Erbb2 (cahErbb2) was the most potent tested mitogen. Persistent expression of cahErbb2 induced CM proliferation, sarcomere loss, and remodeling of tissue structure and function, which were attenuated by small molecule inhibitors of Erk signaling. These results suggest transient activation of Erbb2/Erk axis in cardiomyocytes as a potential strategy for regenerative heart repair.

cell biology↗