Unexpected effects of enhancer-promoter distance uncover co-transcriptional genome surveillance by HUSH
Abstract/Contents
- Abstract
- The human silencing hub (HUSH) complex has emerged as a central mechanism for protecting vertebrate genomes against the invasion of active transposons, retroviruses, and transgenes due to its unique ability to detect and repress mobile elements without prior exposure to their sequences. Recent studies revealed that HUSH recruitment is dependent on transcription, but a unifying molecular mechanism by which HUSH identifies its targets as 'non-self' DNA and selects them for silencing remains unknown. As part of my PhD work, I combined diverse genetic, genomic, and biochemical approaches to reveal co-transcriptional genome surveillance and RNAi-independent silencing by HUSH. First, I made the fortuitous discovery that deletion of a gene desert separating the Sox2 gene and its super-enhancer in mouse embryonic stem cells (ESCs) induces transcriptional silencing (TGS), which I subsequently showed through a genetic screen to be HUSH-dependent. Harnessing this de novo silencing event, I uncovered two distinct modes of HUSH function -- one involved co-transcriptional surveillance in the absence of silencing, while the other was associated with H3K9me3 deposition and repression. We found that HUSH travels with elongating RNA polymerase II (RNAPII), interacts with the transcriptional termination machinery, and accumulates on chromatin in a manner dependent on the termination factor WDR82. Perturbation of endogenous termination signals allowed us to trigger the switch from HUSH surveillance to silencing. The existence of TGS in mammals has long remained controversial, because in contrast to many other organisms, mammals lack the RNA-dependent RNA polymerase (RdRP) that amplifies the RNAi response. This work demonstrates that co-transcriptional genome silencing by HUSH represents an RNAi-independent TGS mechanism in mammals in which discernment of "self" from "non-self" is coupled to the fundamental process of transcription termination.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Spencley, Andrew Lewis |
|---|---|
| Degree supervisor | Wysocka, Joanna, Ph. D. |
| Thesis advisor | Wysocka, Joanna, Ph. D. |
| Thesis advisor | Bassik, Michael |
| Thesis advisor | Straight, Aaron, 1966- |
| Thesis advisor | Winslow, Monte |
| Degree committee member | Bassik, Michael |
| Degree committee member | Straight, Aaron, 1966- |
| Degree committee member | Winslow, Monte |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Andrew Spencley. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/gw995cb2122 |
Access conditions
- Copyright
- © 2022 by Andrew Lewis Spencley
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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