scholarly journals Vincent Cristofalo “Rising Star”Award: DNA Methylation Landscapes in Aging

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 386-386
Author(s):  
Morgan Levine
Keyword(s):  
Recent Work ◽  
Tissue Level ◽  
Epigenetic Alterations ◽  
Disease Etiology ◽  
Cellular Processes ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Epigenetic Code ◽  
Yamanaka Factors ◽  
Induced Pluripotent

Abstract The epigenetic code can be thought of as the operating system of the cell. It controls the most basic and critical cellular processes including differentiation, replication, metabolism, and signaling. Yet, with age, the epigenetic landscape is remodeled, bringing about widespread consequences for cellular and tissue identity, integrity, and functioning. But, what if like computer programmers, we could discover how to recode or restore the original program? The revolutionary discoveries by Yamanaka and Takahashi suggests this may be possible. While early experiments showed that Yamanaka factors could be used to convert somatic cells into induced pluripotent stem cells, more recent work by us and others have shown that signatures of epigenetic aging are also wiped clean during this process. What’s more, epigenetic age reversal appears to take place early in the process and thus can be achieved without the cell _needing to dedifferentiate. Building off of this discovery, our lab is combining novel experiments and advanced bioinformatic techniques to decipher the epigenetic code and determine how it is remodeled during aging, development, and reprogramming. In our recent work, we have made advancements in mapping the epigenetic alterations observed in aging and linking them to both cellular processes and disease etiology. We have identified specific age changes in mouse and human cells that reflect mitotic history, cellular senescence, oxidative damage, and mitochondrial dysfunction. We have also demonstrated that these changes inform differences in organismal lifespan and/or disease etiology at the tissue level. Overall, this work has sweeping implications for our basic understanding of epigenetic aging and reprogramming, and will help provide the foundation for potent therapeutics that extend healthspan and lifespan.

scholarly journals Temporal mechanisms of myogenic specification in human induced pluripotent stem cells

2021 ◽  
Vol 7 (12) ◽  
pp. eabf7412
Author(s):  
P. Nayak ◽  
A. Colas ◽  
M. Mercola ◽  
S. Varghese ◽  
S. Subramaniam
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Patient Specific ◽  
Cellular Processes ◽  
Transcriptional Cofactors ◽  
Extracellular Matrix Components ◽  
Cell Subpopulations ◽  
Longitudinal Comparison ◽  
Induced Pluripotent

Understanding the mechanisms of myogenesis in human induced pluripotent stem cells (hiPSCs) is a prerequisite to achieving patient-specific therapy for diseases of skeletal muscle. hiPSCs of different origin show distinctive kinetics and ability to differentiate into myocytes. To address the unique cellular and temporal context of hiPSC differentiation, we perform a longitudinal comparison of the transcriptomic profiles of three hiPSC lines that display differential myogenic specification, one robust and two blunted. We detail temporal differences in mechanisms that lead to robust myogenic specification. We show gene expression signatures of putative cell subpopulations and extracellular matrix components that may support myogenesis. Furthermore, we show that targeted knockdown of ZIC3 at the outset of differentiation leads to improved myogenic specification in blunted hiPSC lines. Our study suggests that β-catenin transcriptional cofactors mediate cross-talk between multiple cellular processes and exogenous cues to facilitate specification of hiPSCs to mesoderm lineage, leading to robust myogenesis.

Maternal Dietary Fatty Acid Composition and Newborn Epigenetic Aging—A Geometric Framework Approach

2021 ◽  
Author(s):  
Nicholas A Koemel ◽  
Alistair M Senior ◽  
Hasthi U Dissanayake ◽  
Jason Ross ◽  
Rowena L McMullan ◽  
...  
Keyword(s):  
Newborn Infants ◽  
Intima Media Thickness ◽  
Response Surfaces ◽  
Geometric Framework ◽  
Body Fatness ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Framework Approach ◽  
Epigenetic Age Acceleration ◽  
Aortic Intima

Abstract Background Maternal nutrition is associated with epigenetic and cardiometabolic risk factors in offspring. Research in humans has primarily focused on assessing the impact of individual nutrients. Objective We sought to assess the collective impact of maternal dietary monounsaturated (MUFA), polyunsaturated (PUFA), and saturated fat (SFA) on epigenetic aging and cardiometabolic risk markers in healthy newborn infants using a geometric framework approach. Design Body fatness (n = 162), aortic intima-media thickness (n = 131), heart rate variability (n = 118), and epigenetic age acceleration (n = 124) were assessed in newborn infants. Maternal dietary intake was cross-sectionally assessed in the immediate postpartum period via a validated 80-item self-administered food-frequency questionnaire. Generalized additive models were used to explore interactive associations of nutrient intake, with results visualized as response surfaces. Results After adjustment for total energy intake, maternal age, gestational age, and sex there was a 3-way interactive association of MUFA, PUFA, and SFA (P = 0.001) with newborn epigenetic aging. This suggests that the nature of each fat class association depends upon one another. Response surfaces revealed MUFA was positively associated with newborn epigenetic age acceleration only at proportionately lower intakes of SFA or PUFA. We also demonstrate a potential beneficial association of omega-3 PUFA with newborn epigenetic age acceleration (P = 0.008). There was no significant association of fat class with newborn aortic intima-media thickness, heart rate variability, or body fatness. Conclusions In this study, we demonstrate an association between maternal dietary fat class composition and epigenetic aging in newborns. Future research should consider other characteristics such as the source of maternal dietary fatty acids.

scholarly journals Lymphatic Vascular Structures: A New Aspect in Proliferative Diabetic Retinopathy

2018 ◽  
Vol 19 (12) ◽  
pp. 4034 ◽  
Author(s):  
Erika Gucciardo ◽  
Sirpa Loukovaara ◽  
Petri Salven ◽  
Kaisa Lehti
Keyword(s):  
Diabetic Retinopathy ◽  
Ex Vivo ◽  
Tissue Level ◽  
Clinical Samples ◽  
Related Factors ◽  
Disease Etiology ◽  
Working Age ◽  
Vascular Structures ◽  
Underlying Mechanisms ◽  
End Stage

Diabetic retinopathy (DR) is the most common diabetic microvascular complication and major cause of blindness in working-age adults. According to the level of microvascular degeneration and ischemic damage, DR is classified into non-proliferative DR (NPDR), and end-stage, proliferative DR (PDR). Despite advances in the disease etiology and pathogenesis, molecular understanding of end-stage PDR, characterized by ischemia- and inflammation-associated neovascularization and fibrosis, remains incomplete due to the limited availability of ideal clinical samples and experimental research models. Since a great portion of patients do not benefit from current treatments, improved therapies are essential. DR is known to be a complex and multifactorial disease featuring the interplay of microvascular, neurodegenerative, metabolic, genetic/epigenetic, immunological, and inflammation-related factors. Particularly, deeper knowledge on the mechanisms and pathophysiology of most advanced PDR is critical. Lymphatic-like vessel formation coupled with abnormal endothelial differentiation and progenitor cell involvement in the neovascularization associated with PDR are novel recent findings which hold potential for improved DR treatment. Understanding the underlying mechanisms of PDR pathogenesis is therefore crucial. To this goal, multidisciplinary approaches and new ex vivo models have been developed for a more comprehensive molecular, cellular and tissue-level understanding of the disease. This is the first step to gain the needed information on how PDR can be better evaluated, stratified, and treated.

scholarly journals HAUSP Is a Key Epigenetic Regulator of the Chromatin Effector Proteins

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 42
Author(s):  
Omeima Abdullah ◽  
Mahmoud Alhosin
Keyword(s):  
Dna Methyltransferase ◽  
Ring Finger ◽  
Effector Proteins ◽  
Histone Deacetylase 1 ◽  
Cellular Processes ◽  
Histone Lysine Methyltransferase ◽  
Epigenetic Code ◽  
Specific Protease ◽  
Lysine Methyltransferase ◽  
Ubiquitin Specific Protease

HAUSP (herpes virus-associated ubiquitin-specific protease), also known as Ubiquitin Specific Protease 7, plays critical roles in cellular processes, such as chromatin biology and epigenetics, through the regulation of different signaling pathways. HAUSP is a main partner of the “Epigenetic Code Replication Machinery,” ECREM, a large protein complex that includes several epigenetic players, such as the ubiquitin-like containing plant homeodomain (PHD) and an interesting new gene (RING), finger domains 1 (UHRF1), as well as DNA methyltransferase 1 (DNMT1), histone deacetylase 1 (HDAC1), histone methyltransferase G9a, and histone acetyltransferase TIP60. Due to its deubiquitinase activity and its ability to team up through direct interactions with several epigenetic regulators, mainly UHRF1, DNMT1, TIP60, the histone lysine methyltransferase EZH2, and the lysine-specific histone demethylase LSD1, HAUSP positions itself at the top of the regulatory hierarchies involved in epigenetic silencing of tumor suppressor genes in cancer. This review highlights the increasing role of HAUSP as an epigenetic master regulator that governs a set of epigenetic players involved in both the maintenance of DNA methylation and histone post-translational modifications.

scholarly journals The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 666 ◽  
Author(s):  
Evangelos Koustas ◽  
Panagiotis Sarantis ◽  
Athanasios G. Papavassiliou ◽  
Michalis V. Karamouzis
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Epigenetic Alterations ◽  
Primary Resistance ◽  
Cellular Processes ◽  
Mutational Burden ◽  
Number Of Patients ◽  
Tumor Mutational Burden

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.

Intestinal Iron Absorption: Cellular Mechanism and Regulation

Physiology ◽  
1997 ◽  
Vol 12 (4) ◽  
pp. 184-189
Author(s):  
ES Debnam ◽  
SKS Srai
Keyword(s):  
Recent Work ◽  
Brush Border ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Cellular Mechanism ◽  
Iron Transfer ◽  
Intestinal Iron Absorption ◽  
Body Iron ◽  
Cellular Processes

Enterocyte iron transfer is crucial for body iron homeostasis, but the cellular processes involved are poorly understood. Recent work suggests the response to increased iron demand involves upregulation of transport at the brush border together with decreased translation of ferritin mRNA, thereby facilitation iron transfer to the blood.

Pathogenic Mechanisms

2014 ◽  
Author(s):  
Alis Hughes ◽  
Lesley Jones
Keyword(s):  
Cag Repeat ◽  
Therapeutic Interventions ◽  
Mutant Huntingtin ◽  
Repeat Instability ◽  
Disease Etiology ◽  
Pathogenic Mechanisms ◽  
Rna Toxicity ◽  
Cellular Processes ◽  
Protein Clearance ◽  
Individual Importance

Huntington’s disease (HD) pathogenesis is complex. In the two decades since the gene and its mutation were discovered, there has been extensive exploration of how the expanded CAG repeat in HTT leads to neurodegeneration in HD. This chapter focuses on the mechanisms that potentially contribute to the dysfunction and death of cells in HD. These include repeat instability and RNA toxicity and the production, processing, modification, and degradation of mutant huntingtin. The effects of mutant HTT on cellular processes such as transcription, transport, neurotransmission, and protein clearance are also described. The interdependence and individual importance of these mechanisms in disease etiology remains to be clarified; however, consideration of each could be important for the development of therapeutic interventions in HD.

Epigenetic Biomarkers Are Applicable for Risk Stratification in Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3194-3194 ◽  
Author(s):  
Anna Mies ◽  
Tanja Božić ◽  
Michael Kramer ◽  
Julia Franzen ◽  
Gerhard Ehninger ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Somatic Mutations ◽  
Chronological Age ◽  
Prognostic Impact ◽  
Cpg Site ◽  
Epigenetic Biomarkers ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Dnam Level

Abstract Introduction: Myelodysplastic syndromes (MDS) are frequently associated with somatic mutations in epigenetic modifiers such as de novo methyltransferase 3A (DNMT3A). However, so far the significance of specific epigenetic modifications for disease stratification remains largely unknown. In this study, we investigated if epigenetic biomarkers, which were previously described to be relevant in acute myeloid leukemia (AML), are also of prognostic impact in MDS. Methods: Peripheral blood samples of MDS patients (n=126; f/m=59/67; median age 66; range 26-93) equally distributed across all risk groups based on the revised International Prognostic Scoring System (IPSS-R; very low/low=43; int=37; high/very high=43; n.a.=3) were analyzed at initial diagnosis. Genomic DNA was isolated, bisulfite converted, and DNA methylation (DNAm) level at selected genomic regions were determined by pyrosequencing as described before: (1) hypermethylation at a CpG site in complement component 1 subcomponent R (C1R), (2) an epigenetic age prediction with an Epigenetic-Aging-Signature based on three CpG sites located in the genes ITGA2B, ASPA and PDE4C, and (3) an epimutation in the DNMT3A locus, mimicking somatic mutations of this gene, were all reported to correlate with overall survival (OS) in AML patients. Results were subsequently compared to clinical parameters such as IPSS-R, leukemic progression, and OS. Results: A clear tendency for longer OS of MDS patients was observed if DNAm level at C1R was above median (22%; two-year survival 67% [95% CI 53-84%] in hypo- vs. 84% [95% CI 74-95%] in hypermethylated samples; P=0.071), which is in line with previous findings in AML samples. The predicted epigenetic age determined by the Epigenetic-Aging-Signature correlated moderately with the chronological age of the investigated MDS patients (R=0.42) and their OS (P=0.029). This effect was also seen in a multivariable analysis of this cohort including predicted and chronological age (P=0.040). Finally, we stratified MDS patients by the DNAm level of 10% in DNMT3A. Similar to AML, also MDS patients with higher methylation at the CpG site represented on a microarray (cg23009818) showed in tendency shorter OS (two-year survival 79% [95% CI 69-89%] in hypo- vs. 65% [95% CI 45-93%] in hypermethylated samples; P=0.110). In fact, this association was even more pronounced at a neighboring CpG site (two-year survival 83% [95% CI 74-92%] in hypo- vs. 49% [95% CI 29-84%] in hypermethylated samples; P=0.009; Figure A). Moreover, increased DNAm level at this neighboring CpG site in DNMT3A was indicative for progression into AML (after two years: 15% [95% CI 6-24%] in hypo- vs. 44% [95% CI 12-76%] in hypermethylated samples; P=0.011; Figure B). Of note, none of these markers correlated with IPSS-R categories indicating that they might provide independent prognostic parameters. Conclusion: The analyzed epigenetic biomarkers revealed prognostic relevance in MDS patients and we suggest considering them in future risk stratification models. Particularly the aberrant hypermethylation of DNMT3A, which may also result in alternative splicing of DNMT3A transcripts, was associated with accelerated leukemic progression and shorter OS. Figure Figure. Disclosures Božić: Cygenia GmbH: Consultancy. Wagner:Cygenia GmbH: Equity Ownership.

scholarly journals The costs of competition: high social status males experience accelerated epigenetic aging in wild baboons

2020 ◽  
Author(s):  
Jordan A. Anderson ◽  
Rachel A. Johnston ◽  
Amanda J. Lea ◽  
Fernando A. Campos ◽  
Tawni N. Voyles ◽  
...  
Keyword(s):  
Dominance Rank ◽  
Natural Populations ◽  
Life History Strategy ◽  
Male Dominance ◽  
Biological Aging ◽  
Epigenetic Clock ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Aging Rates ◽  
Young Life

AbstractAging, for virtually all life, is inescapable. However, within populations, biological aging rates vary. Understanding sources of variation in this process is central to understanding the biodemography of natural populations. We constructed a DNA methylation-based age predictor for an intensively studied wild baboon population in Kenya. Consistent with findings in humans, the resulting “epigenetic clock” closely tracks chronological age, but individuals are predicted to be somewhat older or younger than their known ages. Surprisingly, these deviations are not explained by the strongest predictors of lifespan in this population, early adversity and social integration. Instead, they are best predicted by male dominance rank: high-ranking males are predicted to be older than their true ages, and epigenetic age tracks changes in rank over time. Our results argue that achieving high rank for male baboons—the best predictor of reproductive success—imposes costs consistent with a “live fast, die young” life history strategy.

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