Control of transcriptional programs of aging by NF-kappaB
Abstract/Contents
- Abstract
- Aging is a degenerative process accompanied by tissue deterioration, decline in function and increased susceptibility to disease. It is now understood to be a genetically and environmentally regulated process, rather than simply the result of wear and tear. We developed a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms, and identified the transcription factor NF-[kappa]B as a candidate regulator of aging. Using multiple independent models, we show a role for NF-[kappa]B in regulating transcriptional programs of aging. First, we found that aged mice subjected to NF-[kappa]B blockade for two weeks exhibit reversion of the tissue characteristics and global gene expression programs to those of young mice. Next, we detected deregulated transcriptional activity of NF-[kappa]B in Sirt6-deficient mice, which exhibit premature aging-like symptoms. We show that Sirt6 interacts with the NF-[kappa]B RelA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-[kappa]B target gene promoters. Computational genomics analyses revealed increased activity of NF-[kappa]B-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice, suggesting that hyperactive NF-[kappa]B-dependent transcription in the absence of Sirt6 promotes premature aging-like syndromes. Finally, we performed a genome-scale survey of RelA and Sirt6 location on chromatin in mouse embryonic fibroblasts (MEFs) via chromatin immunoprecipiation (ChIP)-on-chip to understand to what extent Sirt6 and RelA act coordinately to regulate gene expression. These results indicate that RelA and Sirt6 co-occupy the promoters of a large population of genes at sites less than 500kb apart and/or require RelA to enable binding of Sirt6. Expression analysis of these shared targets reveals direct regulation of 301 promoters, including genes such as Shc1 (encoding p66), Cdkn2a (encoding p16), Wnt2 and Jmjd3, which have been separately implicated in the aging process. We propose that hyperactive NF-[kappa]B signaling contributes to premature and normal aging.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Kawahara, Tiara Lynn Aiko |
|---|---|
| Associated with | Stanford University, Department of Cancer Biology. |
| Primary advisor | Chang, Howard Y. (Howard Yuan-Hao), 1972- |
| Thesis advisor | Chang, Howard Y. (Howard Yuan-Hao), 1972- |
| Thesis advisor | Chua, Katrin Faye |
| Thesis advisor | Khavari, Paul A |
| Thesis advisor | Sweet-Cordero, Eric |
| Advisor | Chua, Katrin Faye |
| Advisor | Khavari, Paul A |
| Advisor | Sweet-Cordero, Eric |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Tiara Lynn Aiko Kawahara. |
|---|---|
| Note | Submitted to the Department of Cancer Biology. |
| Thesis | Ph.D. Stanford University 2010 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Tiara Lynn Aiko Kawahara
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...