# Epigenetics in the extreme - investigating heritability driven by disordered RNA binding proteins in development and cancer

> **NIH NIH R00** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $49,220

## Abstract

Heritable protein conformations, ‘prions’, were discovered as the cause of debilitating
transmissible spongiform encephalopathies. Long considered to be a fascinating biological oddity,
the recent discovery of prions in diverse organisms from fungi to sea slugs has led to the
watershed realization that ‘protein-based genes’ are much more common than previously
appreciated. We recently discovered that intrinsically disordered proteins can drive the formation
of such protein-based molecular memories that can be epigenetically inherited over hundreds of
generations without any alteration to its genome sequence. RNA binding proteins are particularly
enriched in this dataset. An emergent area of study has demonstrated that disordered regions in
RNA binding proteins are very common and often drives the formation of liquid-liquid de-mixing
states critical for forming membrane-less organelles. My preliminary studies establish that
disordered RNA binding proteins are uniquely poised to relay changes in environment to an
altered cellular program. I will address the following aims during my remaining mentored training
and initial independent research career: 1. To determine the biochemical and functional
implication of intrinsically disordered regions of RNA binding proteins. I have developed a
methodology to quantitatively investigate RNA-protein interactions across a genome. Coupling
this platform with a robust system that I have developed to purify these intrinsically disordered
RNA binding proteins, I intend to biochemically investigate the effect of intrinsically disordered
regions on RNA binding proteins. Additionally, I will examine the effect of these disordered
domains on phenotype using quantitative genetics and cell biology. Finally, I will extend the
method to the human exome to interrogate human RBPs and their frequent oncogenic mutants.
2. To investigate the prion-like behavior of transient overexpression of disordered RNA
binding protein ySmaug. Using high-throughput gene expression analysis, quantitative genetics
and cell biology, I will examine the prion-like behavior of an evolutionarily ancient and highly
disordered RNA binding protein ySmaug. 3. To establish the mechanism of assembly and
transmission of prion-like RBPs. Using toolkits of biochemistry, microscopy and structural
biology (NMR & EM methodologies), I will establish the mechanistic basis of assembly and
transmission of these prion-like RBPs that exhibit canonical genetic hallmarks of prions but
surprisingly do not form amyloids. 4. To investigate the impact of overexpression of
disordered oncogenic proteins. Finally, I will harness a defining property of all known prions –
protease resistance to examine the impact of three disordered nucleic acid binding proteins – p53
(one of its hotspot mutants is known to form amyloid fibers), SAMD4A (human homolog of
ySmaug) and Musashi RNA binding proteins (Msi1 & Msi2) that is overexpressed in a variety of
cancers and been attributed to ...

## Key facts

- **NIH application ID:** 10382634
- **Project number:** 4R00GM128180-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Anupam Kumar Chakravarty
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $49,220
- **Award type:** 4N
- **Project period:** 2018-09-01 → 2021-11-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10382634

## Citation

> US National Institutes of Health, RePORTER application 10382634, Epigenetics in the extreme - investigating heritability driven by disordered RNA binding proteins in development and cancer (4R00GM128180-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10382634. Licensed CC0.

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