# Epigenetic and Metabolic Regulation of Gene Silencing in Saccharomyces

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $708,825

## Abstract

This application for a MIRA award seeks to consolidate the research in the PI's lab, funded by
GM31105 Genetic Analysis of Genes Controlling a Position Effect, currently in its 37th year, and by
GM120374 Metabolism and Epigenetics, currently in its fourth year, into one program. The work
supported by these grants has produced a continuous series of fundamental discoveries about
mechanisms of heterochromatic gene silencing, its epigenetic inheritance, and its sensitivity to
metabolism. Most recently, these efforts have also included the development of transformative new
genetic technologies, and the successful launch of a comprehensive investigation of the impact of
metabolism on epigenetic processes, with an initial focus on those metabolism-altering mutations that
are drivers of human cancers. The long legacy of GM31105 enabled the discovery of how the Sir genes
control heterochromatin formation, the role of silencers in controlling gene expression, and the
epigenetic inheritance of transcriptional states. Many ancillary discoveries made in the course of these
investigations include (1) the first mutations defining the Origin Recognition Complex, and its separable
roles in DNA replication and regulating transcription; (2) defining the molecular topography of
heterochromatin; (3) single-cell assays revealing heterochromatin dynamics; and (4) discovery of
unusual sterile mutations that led to the discovery of protein prenylation of a-factor and Ras. Recently,
the work supported by GM120374 led to the discovery that mutations in components of the Krebs cycle
that function as cancer driver mutations have unexpected impacts on histone demethylases and gene
silencing, and identified new metabolic links to heterochromatin stability. Together, these grants have
produced a transformative technique for the locus-specific labeling of individual nucleosomes that
allowed resolution of one of the longest unsolved questions regarding chromatin, showing that
individual nucleosome retain their genomic addresses through multiple DNA replication cycles. The
newest data from these grants force a fundamental reconsideration of whether nucleosomes are the
carriers of the memory of epigenetic states.
 The proposed research program will answer multiple long-standing questions in epigenetics
such as determining where the memory component resides that allows epigenetic inheritance of
transcriptional states and resolving the mechanism of that memory. In addition, the proposed research
will resolve the mechanism by which gene silencing spreads laterally from its sites of nucleation. The
cell-cycle requirements for the creation of new cell-type-specific states of gene expression will be
identified. Finally, the mechanism by which the newly identified metabolic impacts on epigenetic
silencing will be determined.

## Key facts

- **NIH application ID:** 10085537
- **Project number:** 1R35GM139488-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** JASPER D RINE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $708,825
- **Award type:** 1
- **Project period:** 2021-02-02 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085537

## Citation

> US National Institutes of Health, RePORTER application 10085537, Epigenetic and Metabolic Regulation of Gene Silencing in Saccharomyces (1R35GM139488-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085537. Licensed CC0.

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