ETS2

Protein C-ets-2

Publications

FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16 increase.

PubMed

Full text

Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16 , a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16 expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16 promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3-ETS2-p16 axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.

Keywords

• neurodegenerative disease
• neuronal differentiation
• neuronal senescence
• response mechanisms
• temporal dynamics

The Gene-Regulatory Footprint of Aging Highlights Conserved Central Regulators.

PubMed

Full text

Many genes and pathways have been linked to aging, yet our understanding of underlying molecular mechanisms is still lacking. Here, we measure changes in the transcriptome, histone modifications, and DNA methylome in three metabolic tissues of adult and aged mice. Transcriptome and methylome changes dominate the liver aging footprint, whereas heart and muscle globally increase chromatin accessibility, especially in aging pathways. In mouse and human data from multiple tissues and regulatory layers, age-related transcription factor expression changes and binding site enrichment converge on putative aging modulators, including ZIC1, CXXC1, HMGA1, MECP2, SREBF1, SREBF2, ETS2, ZBTB7A, and ZNF518B. Using Mendelian randomization, we establish possible epidemiological links between expression of some of these transcription factors or their targets, including CXXC1, ZNF518B, and [[BBC3]], and longevity. We conclude that conserved modulators are at the core of the molecular footprint of aging, and variation in tissue-specific expression of some may affect human longevity.

Keywords

• Mendelian randomization
• aging
• epigenome
• gene regulation
• histone modification
• human genetics
• metabolism
• methylome
• transcription factor
• transcriptome