Understanding the role of histone H3 lysine 36 methylation in chromatin regulation and cancer
Abstract/Contents
- Abstract
- Methylation of histone H3 at lysine 36 (H3K36) is found at gene bodies of actively transcribed genes, but the state of methylation at this residue defines distinct biological outcomes. Trimethylation of this site (H3K36me3), which is mediated by the KMT SETD2 in humans, is involved in regulation of RNA processing. Loss of SETD2 and H3K36me3 is a recurring phenomenon in clear cell renal cell carcinoma (ccRCC) and other cancers, suggesting a tumor suppressor role for SETD2. In contrast, the specific molecular functions associated with H3K36me2 are unclear. However, elevated levels of this modification lead to aberrant activation of normally silenced genes, and upregulation of this mark is linked with numerous cancer types including acute myeloid leukemia, multiple myeloma, lung cancers, breast cancers, and glioblastomas. Given their clear implications for opposing roles in disease, it is important to understand the molecular functions of H3K36me2 and H3K36me3 in both their normal physiological roles and disease states. In my thesis, I first compare the roles of H3K36me2 and H3K36me3 in the regulation of actively transcribed genes. Using analyses of RNA-seq datasets from cells depleted of each modification, I show H3K36me3, but not H3K36me2, plays an important role in regulating gene expression and splicing processes. Then, I characterize the effects of H3.3 K36M, an oncohistone, on global regulation of H3K36 methylation. I demonstrate that this mutation depletes not only H3K36me3 (as previously reported) but also H3K36me2, and that the K36M mutant mimics loss of H3K36me2 alone in proliferation assays. Assaying H3K27me3 levels under H3K36 depletion indicates that the crosstalk between H3K27 and K3K36 methylation is largely mediated by H3K36me2, not me3 as previously assumed. This work points to an important role of H3K36me2, not just H3K36me3, in the dysregulation of chromatin modifications mediated by the H3.3 K36M oncohistone. Lastly, I identify the first reader for the H3K36me2 modification. I show that a PWWP domain on the NSD2 protein preferentially binds to H3K36me2. This PWWP-H3K36me2 interaction seems to be important for the stability of NSD2 at chromatin, as well as its ability to increase global H3K36me2 levels in cells and promote cell proliferation. Based on these data, I propose a model for H3K36me2 propagation by NSD2 sensing its own catalytic product and spreading it through chromatin regions.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Sankaran, Saumya M |
|---|---|
| Associated with | Stanford University, Department of Biology. |
| Primary advisor | Gozani, Or Pinchas |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Chua, Katrin Faye |
| Thesis advisor | Morrison, Ashby J |
| Thesis advisor | Sage, Julien |
| Advisor | Chua, Katrin Faye |
| Advisor | Morrison, Ashby J |
| Advisor | Sage, Julien |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Saumya M. Sankaran. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Saumya Sankaran
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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