Abstract PR03: Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for DNA methylation maintenance
Bibliographic record
Abstract
Abstract DNA methylation and histone post-translational modifications (PTMs) represent two key epigenetic regulators of DNA information in chromatin. The faithful inheritance of DNA methylation is essential for normal mammalian development and long-term transcriptional silencing, and aberrant DNA methylation patterns are a hallmark of many cancers. Histone PTMs can alter the physical structure of chromatin and have been proposed to function in the context of a “histone code” to coordinate the recruitment of effector proteins that elicit selective effects on chromatin-templated cellular processes like gene transcription and DNA repair. Indeed, defects in histone recognition by effector proteins are also emerging as underlying causes of cancer initiation and progression. Effector proteins often contain multiple chromatin binding domains. While significant progress has been made characterizing individual effector domains, the role of paired domains and how they function in a combinatorial fashion within chromatin is poorly defined. The E3 ubiquitin ligase UHRF1 is a unique chromatin effector protein, in that it integrates the recognition of both histone PTMs and DNA methylation. We recently showed that H3K9 methyl binding by the tandem Tudor domain (TTD) of UHRF1 is required for DNA methylation maintenance in cancer cells — yet the function of its adjacent plant homeodomain (PHD) in this process was unknown. Here we show that the linked TTD and PHD of UHRF1 operate as a single functional unit in cells, providing a defined combinatorial readout of the modification state of the histone H3 tail that is essential for UHRF1-directed DNA methylation maintenance by DNMT1. These findings provide critical support for the ‘histone code' hypothesis, demonstrating that multivalent histone engagement plays a fundamental role in driving a downstream biological event in chromatin and suggest UHRF1 may be a favorable therapeutic target for regulating aberrant DNA methylation in cancers. This abstract is also presented as Poster B26. Citation Format: Scott B. Rothbart, Bradley M. Dickson, Michelle S. Ong, Krzysztof Krajewski, Scott Houliston, Dmitri B. Kireev, Cheryl H. Arrowsmith, Brian D. Strahl. Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for DNA methylation maintenance. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR03.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".