# Understanding prion-mediated transcriptional modifications and cellular phenotypes: insights into the role of Swi1 prion and prion-like behaviors of BAF proteins

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $322,962

## Abstract

The term "prion" was originally coined to describe the agent responsible for neurodegenerative diseases
associated with the prion protein, PrP. This concept has now broadened to encompass a wide range of proteins
in various organisms, linked to crucial cellular functions or diseases. For example, human pathogenic proteins
like Aβ, tau, α-synuclein and p53 in cancer and neurodegeneration have been proposed to follow prion-like
mechanisms. However, the precise role of prions in these proteinopathies remains unclear. Yeast is a valuable
platform for prion research, with several prion proteins acting as transcription modulators. One notable example
is [SWI+], the prion form of Swi1, a component of the chromatin remodeling complex SWI/SNF. Despite clear
evidence of [SWI+] significantly impacting transcription, the underlying mechanism remains elusive. Moreover,
whether Swi1 orthologs or other components of the human SWI/SNF (also termed BAF) complexes can undergo
prion-like conformational changes has yet to be investigated. Understanding this is vital because SWI/SNF
complexes play a crucial role in transcription regulation, and BAF mutations are implicated in over 20% of tumor
cases and numerous neurological diseases. The long-term goal of our research is to uncover the link between
prions and BAF complexes and contribute to novel therapeutic strategies for related diseases. Specifically, this
project aims to determine if [SWI+] exists in "variants" that produce distinct transcriptomic and phenotypic effects.
Additionally, we aim to understand how [SWI+] alters the structure and activities of SWI/SNF, and induces
abnormal protein interactions and heterotypic protein aggregation, ultimately leading to transcriptomic and
phenotypic changes. Furthermore, we aim to investigate whether any BAF proteins or their mutants exhibit prion-
like behaviors. Our studies have far-reaching implications for other prion-based models and are highly relevant
to human health. To achieve our research goals, we will employ a range of techniques. For Aim 1, we will use
classical genetic and biochemical manipulations, RNA-seq, and functional assays to characterize [SWI+] variants.
For Aim 2, we will utilize immunopurification, quantitative mass spectrometry (MS), ATPase assays, ChIP-seq,
and reChIP-seq to examine the impact of [SWI+] on SWI/SNF architecture and functions. Meanwhile, we will
employ differential centrifugation combined with MS to identify the [SWI+] aggregome and perform genetic and
cellular assays to investigate the interaction mechanism among the aggregomic components. For Aim 3, we will
examine prion-like domains (PrLDs) of BAF proteins for fibrillization in vitro and prionogenicity in yeast. We will
also develop human cell lines with EGFP-based prion reporters to screen for prions of full-length BAF proteins
and their mutants and investigate whether their prion conversion can be promoted by the generated in vitro fibrils
and yeast prion lysates originating...

## Key facts

- **NIH application ID:** 10939741
- **Project number:** 1R01GM155872-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Zhiqiang Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $322,962
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939741

## Citation

> US National Institutes of Health, RePORTER application 10939741, Understanding prion-mediated transcriptional modifications and cellular phenotypes: insights into the role of Swi1 prion and prion-like behaviors of BAF proteins (1R01GM155872-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10939741. Licensed CC0.

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