Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome

Heyn, Holger; Morán, Sebastian; Esteller, Manel

doi:10.4161/epi.23366

Cited by 96 publications

(65 citation statements)

References 21 publications

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“…BAF interacts with several partners, among them A-and B-type lamins, NuMA, and influences active or silencing marks of histones [269,270]. Aberrant DNA methylation profiles, in particular targeting the NFB signaling pathway, are among the other epigenetic modifications in cells from HGPS and Werner syndrome patients [271].…”

Section: Dna Replication Transcription Repair and Epigenetic Defectmentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features associated to progeria. New therapeutic strategies under study, in particular targeting the protein expression pathway at the mRNA level, have shown a remarkable efficacy both in vitro in cells and in vivo in mice models. Strategies intending to clear the toxic accumulated proteins from the nucleus are also under evaluation. However, although exceedingly rare, improving our knowledge of genetic progeroid syndromes and searching for innovative and efficient therapies in these syndromes is of paramount importance as, even before they can be used to save lives, they may significantly (i) expand the affected childrens' lifespan and preserve their quality of life; (ii) improve our understanding of aging-related disorders and other more common diseases; and (iii) expand our fundamental knowledge of physiological aging and its links with major physiological processes such as those involved in oncogenesis.

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Section: Dna Replication Transcription Repair and Epigenetic Defectmentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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“…More recently, it has been observed that CpG sites in HGPS cells gain methylation when compared to hypomethylated control regions but lose methylation when compared to hypermethylated control regions [23]. Again, the trend is a homogeneous redistribution of epigenetic markers in HGPS specimens.…”

Section: Dna Methylationmentioning

confidence: 91%

Epigenetic Involvement in Hutchinson-Gilford Progeria Syndrome: A Mini-Review

et al. 2014

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare human genetic disease that leads to a severe premature ageing phenotype, caused by mutations in the LMNA gene. The LMNA gene codes for lamin-A and lamin-C proteins, which are structural components of the nuclear lamina. HGPS is usually caused by a de novo C1824T mutation that leads to the accumulation of a dominant negative form of lamin-A called progerin. Progerin also accumulates physiologically in normal ageing cells as a rare splicing form of lamin-A transcripts. From this perspective, HGPS cells seem to be good candidates for the study of the physiological mechanisms of ageing. Progerin accumulation leads to faster cellular senescence, stem cell depletion and the progeroid phenotype. Tissues of mesodermic origin are especially affected by HGPS. HGPS patients usually have a bad quality of life and, with current treatments, their life expectancy does not exceed their second decade at best. Though progerin can be expressed in almost any tissue, when death occurs, it is usually due to cardiovascular complications. In HGPS, severe epigenetic alterations have been reported. Histone-covalent modifications are radically different from control specimens, with the tendency to lose the bipartition into euchromatin and heterochromatin. This is reflected in an altered spatial compartmentalization and conformation of chromatin within the nucleus. Moreover, it seems that microRNAs and microRNA biosynthesis might play a role in HGPS. Exemplary in this connection is the suggested protective effect of miR-9 on the central nervous system of affected individuals. This mini-review will report on the state of the art of HGPS epigenetics, and there will be a discussion of how epigenetic alterations in HGPS cells can alter the cellular metabolism and lead to the systemic syndrome.

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“…Vogt -Koyanagi -Harada disease is a bilateral, chronic, diffuse granulomatous uveitis with poliosis, vitiligo, central nervous system, and auditory signs. Many researchers, especially Yang's group, have investigated the gene polymorphisms of many factors including IL-17 that are associated with Vogt -Koyanagi -Harada disease in a Chinese Han population (Shu et al 2010) since Yakura et al first reported the HLA-D locus linkage (Yakura et al 1976 (Heyn et al 2013). …”

Section: Acquired Hypopigmentation Disordersmentioning

confidence: 99%

Melanocytes and Their Diseases

Yamaguchi

Hearing

2014

Cold Spring Harbor Perspectives in Medicine

177

118

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Human melanocytes are distributed not only in the epidermis and in hair follicles but also in mucosa, cochlea (ear), iris (eye), and mesencephalon (brain) among other tissues. Melanocytes, which are derived from the neural crest, are unique in that they produce eu-/pheomelanin pigments in unique membrane-bound organelles termed melanosomes, which can be divided into four stages depending on their degree of maturation. Pigmentation production is determined by three distinct elements: enzymes involved in melanin synthesis, proteins required for melanosome structure, and proteins required for their trafficking and distribution. Many genes are involved in regulating pigmentation at various levels, and mutations in many of them cause pigmentary disorders, which can be classified into three types: hyperpigmentation (including melasma), hypopigmentation (including oculocutaneous albinism [OCA]), and mixed hyper-/hypopigmentation (including dyschromatosis symmetrica hereditaria). We briefly review vitiligo as a representative of an acquired hypopigmentation disorder.

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Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome

Cited by 96 publications

References 21 publications

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Epigenetic Involvement in Hutchinson-Gilford Progeria Syndrome: A Mini-Review

Melanocytes and Their Diseases

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