A5035801056- Nuclear Structure and Function
- RNA Research and Splicing
- DNA Repair Mechanisms
- Pluripotent Stem Cells Research
- Ubiquitin and proteasome pathways
- Single-cell and spatial transcriptomics
- CRISPR and Genetic Engineering
- Acute Myeloid Leukemia Research
- Genomics and Chromatin Dynamics
- NF-κB Signaling Pathways
- Mitochondrial Function and Pathology
- Protease and Inhibitor Mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- Telomeres, Telomerase, and Senescence
- RNA Interference and Gene Delivery
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer, Hypoxia, and Metabolism
- Retinoids in leukemia and cellular processes
- Cancer Genomics and Diagnostics
- Immune cells in cancer
- Wnt/β-catenin signaling in development and cancer
- PARP inhibition in cancer therapy
- Genomics, phytochemicals, and oxidative stress
- Genetics, Aging, and Longevity in Model Organisms
- Viral Infectious Diseases and Gene Expression in Insects
Boston Children's Hospital
2018-2022
Harvard University
2018-2020
Universidad de Oviedo
2010-2019
Boston University
2018
Medicina
2015
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates cryptic donor splice site and yields truncated form of prelamin A called progerin. Small amounts progerin are also produced during normal aging. Studies with mouse models HGPS have allowed recent development first therapeutic approaches for this disease. However, none these earlier works addressed aberrant pathogenic splicing observed patients because lack an appropriate model. Here, we...
Alterations in the architecture and dynamics of nuclear lamina have a causal role normal accelerated aging through both cell-autonomous systemic mechanisms. However, precise nature molecular cues involved this process remains incompletely defined. Here we report that accumulation prelamin A isoforms at triggers an ATM- NEMO-dependent signaling pathway leads to NF-κB activation secretion high levels proinflammatory cytokines two different mouse models (Zmpste24(-/-) Lmna(G609G/G609G) mice)....
Mutation accumulation during life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Somatic mutations in blood progenitors provide insight into rate and processes this accumulation, as well developmental lineage tree stem cell division numbers. Here, we catalog genomes of human-bone-marrow-derived umbilical-cord-blood-derived progenitor cells (HSPCs). We find that accumulate gradually with approximately 14 base substitutions per year. The majority...
Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to death, predominantly myocardial infarction or stroke. The goal this study was investigate mechanisms cause in HGPS.We performed expression functional studies wild-type mice knock-in Lmna(G609G/+) expressing progerin, which mimic the main clinical manifestations HGPS. showed aortic...
Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A, an essential component nuclear envelope. Zmpste24-deficient mice exhibit multiple defects that phenocopy human accelerated aging processes such as Hutchinson-Gilford progeria syndrome. In this work, we report progeroid Zmpste24(-/-) present profound transcriptional alterations genes regulate somatotroph axis, together with extremely high circulating levels growth hormone (GH) and drastic reduction...
Communication between the nuclear lamina protein lamin-A and actin cytoskeleton is required for optimal T cell responses.
Metabolic reprogramming strategies focus on the normalization of metabolism cancer cells and constitute promising targets for treatment. Here, we demonstrate that glucose transporter 4 (GLUT4) has a prominent role in basal uptake MCF7 MDA‐MB‐231 breast cells. We show shRNA‐mediated down‐regulation GLUT4 diminishes induces metabolic by reallocating flux to oxidative phosphorylation. This reallocation is reflected an increased activity mitochondrial oxidation pyruvate lower lactate release....
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases HGPS are due to heterozygous silent mutation (c.1824C>T; p.Gly608Gly) that enhances the use an internal 5′ splice site (5′SS) in exon 11 LMNA pre-mRNA and leads production truncated protein (progerin) with dominant negative effect. Here we show changes accessibility 5′SS which sequestered conserved RNA structure. Our results also reveal...
Abstract Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, metalloproteinase mutated human progeria involved nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan serious cell-intrinsic cell-extrinsic alterations restrict application interpretation carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. develop normally keep similar proportions...
Significance Defective prelamin A processing causes cardiovascular alterations and premature death in Hutchinson–Gilford progeria syndrome (HGPS) patients also occurs during physiological aging. We found overt repolarization abnormalities HGPS at advanced disease stages. Similar were present progeroid Zmpste24 −/− mice, which had cardiomyocytes that exhibited prolonged calcium transient duration reduced sarcoplasmic reticulum loading capacity release, consistent with absence of...
Mutations in the nuclear envelope protein lamin A or its processing protease ZMPSTE24 cause human accelerated aging syndromes, including Hutchinson-Gilford progeria syndrome. Similarly, Zmpste24-deficient mice accumulate unprocessed prelamin and develop multiple progeroid symptoms, thus representing a valuable animal model for study of these syndromes. also show marked transcriptional alterations associated with chromatin disorganization, but molecular links between both processes are...
Abstract Matrix metalloproteases (MMPs) regulate innate immunity acting over proinflammatory cytokines, chemokines, and other immune-related proteins. MMP-25 (membrane-type 6-MMP) is a membrane-bound enzyme predominantly expressed in leukocytes whose biological function has remained largely unknown. We have generated Mmp25-deficient mice to elucidate the vivo of this protease. These mutant are viable fertile do not show any spontaneous phenotype. However, Mmp25-null exhibit defective immune...
Summary Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent changes, but mechanism is unknown. Here, we profile lamina‐associated domains ( LAD s) using lamin B1 Ch IP ‐Seq in young old hepatocytes find that, although resides a large fraction both ages, third B1‐associated regions are bound exclusively each age vivo. Regions occupied by solely livers enriched for forkhead motif, Foxa pioneer...