Hutchinson–Gilford progeria syndrome through the lens of transcription

Abstract

SummaryLamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNA gene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.

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

“…The NE shape alterations, protrusions and invaginations, allow the increase in the NE surface area whereas the nuclear volume remains unchanged [213]. Transcription factors regulating gene expression and numerous other proteins are sequestered into lamina and/or mislocalized in laminopathic cells, a phenomenon impairing several aspects of nuclear genome activity [21,33,214,215].…”

Senescencia del sistema inmune y alteraciones relacionadas con el asma

“…Además, existen síndromes de envejecimiento prematuro por mutaciones genéticas como el de Hutchinson-Gilford, o progeria, 3 en el cual el gen muta para la proteína de envoltura nuclear laminina A (LMNA), y el de Werner o progeria adulta, 4 con mutación en el gen WRN que codifica para una proteína esencial para la replicación y reparación del ADN. En ambos, los individuos se vuelven senescentes antes de los 15 años.…”

Epigenetic Changes in Aging and Age-related Disease

“…Progerin accumulates gradually as a physiological consequence of normal aging; however, in HGPS patients, progerin agglomerates at an accelerated rate. Increased levels of nuclear progerin have been linked to many age-related phenotypes including: telomeric aberrations, defective DNA repair, mitochondrial dysfunction, altered cell cycle regulation and cellular senescence [86, 89,90]. Interestingly, the epigenetic architecture of HGPS mimics the epigenetics of normal aging [86].…”

“…In HGPS cells, the non-random arrangement of chromosomes into discrete territories is perturbed due to the presence of abundant progerin. The consequences of such distortion are a loss of peripheral heterochromatin, rampant nuclear disorganization and nuclear lobulation or blebbing [89,94]. Of note, several proteins involved in maintaining nuclear architecture, such as barrier-to-autointegration factor (BAF) [95], inhibitor of growth protein 1 (ING1) [96] and D4Z4 [97], are also frequently lost in progeroid cells.…”