Multi-level transcriptomic analysis ofLMNA-related dilated cardiomyopathy identifies disease-driving processes DOI Open Access
Noam Zuela-Sopilniak, Julien Morival, Jan Lammerding

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 13, 2024

LMNA- related dilated cardiomyopathy ( LMNA -DCM) is one of the most severe forms DCM. The incomplete understanding molecular disease mechanisms results in lacking treatment options, leading to high mortality amongst patients. Here, using an inducible, cardiomyocyte-specific lamin A/C depletion mouse model, we conducted a comprehensive transcriptomic study, combining both bulk and single nucleus RNA sequencing, spanning -DCM progression, identify potential drivers. Our refined analysis pipeline identified 496 genes already misregulated early disease. expression these was largely driven by specific cardiomyocyte sub-populations involved biological processes mediating cellular response DNA damage, cytosolic pattern recognition, innate immunity. Indeed, damage hearts significantly increased correlated with reduced A levels. Activation recognition cardiomyocytes independent cGAS, which rarely expressed cardiomyocytes, but likely occurred downstream other sensors such as IFI16. Altered gene cardiac fibroblasts immune cell infiltration further contributed tissue-wide changes expression. predicted significant alterations cell-cell communication between fibroblasts, cells, mediated through extracellular matrix (ECM) hearts. Taken together, our work suggests model nuclear leads activation responses, pathway, signaling pathways that activate inflammation, recruitment, transcriptional collectively drive pathogenesis.

Язык: Английский

Mechanisms underlining R-loop biology and implications for human disease DOI Creative Commons
Junzhe Liu,

Fengze Li,

Yulong Cao

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Фев. 21, 2025

R-loops are three-stranded non-canonical nucleic acid structures composed of nascent RNA hybridized with the template DNA strand, leaving non-template strand displaced. These play crucial roles in regulating gene expression, replication, and transcription processes. However, have also been increasingly described as highly deleterious, causing genomic instability damage. To maintain at a relatively safe level, complex regulatory mechanisms exist to prevent their excessive formation. The growing understanding R-loop functions has provided valuable insights into structure potential clinical applications. Emerging research indicates that contribute pathogenesis various disorders, including neurodegenerative, immune-related, neoplastic diseases. This review summarizes metabolism its significance etiology associated disorders. By elucidating governing R-loops, we aim establish theoretical foundation for disease exploring novel therapeutic strategies targeting these hybrid structures.

Язык: Английский

Процитировано

1
The Bacterial Second Messenger Cyclic di-AMP and Inflammation DOI
Tiffany M. Zarrella, Guangchun Bai

Inflammation, Год журнала: 2025, Номер unknown, С. 1 - 17

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Clinical Outcome and Molecular Profile in Patients with DDX41 Mutation Hot-Spots: A Letter to the Editor DOI Creative Commons

Nadia Toumeh,

Yazan Jabban,

Ahmad Nanaa

и другие.

Hematology Reports, Год журнала: 2025, Номер 17(3), С. 26 - 26

Опубликована: Май 8, 2025

Background/Objectives:DDX41, DEAD-box RNA helicase 41 gene located on chromosome 5q25.3, is one of the most mutated genes in patients with germline predisposition to myeloid neoplasms. Germline and somatic mutations often have different locations patterns mutation, some hotspots displaying diversity based ethnicity. We aimed explore clinical outcomes various DDX41 hot-spot mutations. Methods: This was a retrospective study at Mayo Clinic mutation identified through Next Generation Sequencing (NGS) between 2018 2024. completed unadjusted comparisons using continuous or categorical variables, survival rates were assessed Kaplan-Meier method cox regression analysis. Results: Overall appears be higher those p.M1| when compared p.Asp140GlyFs*2 p.Arg525His, comparable p.Arg525His p.Asp140GlyFs*2. Among males who underwent bone marrow transplant, transplant appeared lower rates, although not statistically significant. Our limited by small sample size, therefore limiting our ability reach significance. Conclusions: findings suggest potential implications for hot-spots.

Язык: Английский

Процитировано

0
CRISPR RNA-Guided Gene Editing and its Clinical Research Applications in Hematology with Focus on Inherited Germline Predisposition to Hematologic Malignancies DOI Open Access
Rina Kansal

Опубликована: Июнь 10, 2024

Clustered regularly interspaced short palindromic repeats (CRISPR) based gene-editing has begun to transform the treatment landscape of genetic diseases. The history discovery CRISPR/CRISPR-associated (Cas) proteins/single guide RNA (sgRNA)-based since first report repetitive sequences unknown significance in 1987 is fascinating, instructive, and inspiring for future advances. recent approval CRISPR-Cas9-based gene therapy treat patients with severe sickle cell anemia transfusion-dependent beta thalassemia renewed hope treating other hematologic diseases, including germline predisposition malignancies, who would benefit greatly from development CRISPR-based therapies. purpose this manuscript three-fold: first, a chronological description CRISPR-Cas9-sgRNA-based editing; second, brief current state clinical research selected applications diseases therapy; third, progress therapies inherited bone marrow failure syndromes, hopefully stimulate efforts towards developing these syndromes conditions malignancies.

Язык: Английский

Процитировано

2
The CRISPR-Cas System and Clinical Applications of CRISPR-Based Gene Editing in Hematology with a Focus on Inherited Germline Predisposition to Hematologic Malignancies DOI Open Access
Rina Kansal

Genes, Год журнала: 2024, Номер 15(7), С. 863 - 863

Опубликована: Июль 1, 2024

Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history discovery CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based since first report repetitive sequences unknown significance in 1987 is fascinating, highly instructive, and inspiring for future advances medicine. recent approval CRISPR-Cas9-based therapy treat patients with severe sickle cell anemia transfusion-dependent β-thalassemia renewed hope treating other hematologic diseases, including a germline predisposition malignancies, who would benefit greatly from development CRISPR-inspired therapies. purpose this paper three-fold: first, chronological description CRISPR-Cas9-sgRNA-based editing; second, brief current state clinical research selected applications diseases CRISPR-based therapy, preceded by tools being used genome third, presentation progress therapies inherited bone marrow failure syndromes, hopefully stimulate efforts towards developing these syndromes conditions malignancies.

Язык: Английский

Процитировано

2
Multi-level transcriptomic analysis ofLMNA-related dilated cardiomyopathy identifies disease-driving processes DOI Open Access
Noam Zuela-Sopilniak, Julien Morival, Jan Lammerding

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 13, 2024

LMNA- related dilated cardiomyopathy ( LMNA -DCM) is one of the most severe forms DCM. The incomplete understanding molecular disease mechanisms results in lacking treatment options, leading to high mortality amongst patients. Here, using an inducible, cardiomyocyte-specific lamin A/C depletion mouse model, we conducted a comprehensive transcriptomic study, combining both bulk and single nucleus RNA sequencing, spanning -DCM progression, identify potential drivers. Our refined analysis pipeline identified 496 genes already misregulated early disease. expression these was largely driven by specific cardiomyocyte sub-populations involved biological processes mediating cellular response DNA damage, cytosolic pattern recognition, innate immunity. Indeed, damage hearts significantly increased correlated with reduced A levels. Activation recognition cardiomyocytes independent cGAS, which rarely expressed cardiomyocytes, but likely occurred downstream other sensors such as IFI16. Altered gene cardiac fibroblasts immune cell infiltration further contributed tissue-wide changes expression. predicted significant alterations cell-cell communication between fibroblasts, cells, mediated through extracellular matrix (ECM) hearts. Taken together, our work suggests model nuclear leads activation responses, pathway, signaling pathways that activate inflammation, recruitment, transcriptional collectively drive pathogenesis.

Язык: Английский

Процитировано

1