# Harnessing the chromatin conformational code for epigenetic regulation

> **NIH NIH DP2** · STANFORD UNIVERSITY · 2022 · $1,416,600

## Abstract

Project summary
Eukaryotic DNA is wrapped around nucleosomes, which form chains of chromatin that are further folded into
three-dimensional assemblies. The architecture of these assemblies regulates many nuclear functions, including
genome 3D folding and transcription, and ultimately dictates cellular identity. Nucleosomes are a well-known hub
of chromatin regulation, most of which is thought to occur via a variety of post-translational modifications on the
protruding flexible tails of histones. Based on the assumption that most regulation of chromatin's structure and
interactions with other factors occurs at these histone tails, the globular core of nucleosomes has been
considered rigid and minimally regulatory. Excitingly, my recent work has revealed a new insight: that the
nucleosome core is malleable and that this plasticity regulates chromatin folding and gene repression. I therefore
propose that the globular, malleable core of nucleosomes is a hub for genetic and epigenetic regulation as well
as a potential novel therapeutic target. To test this provocative hypothesis that challenges the textbook paradigm
of chromatin regulation, novel tools capable of probing both in vitro and in vivo atomic-scale dynamics of large
macromolecular assemblies such as chromatin must be developed. My lab will close this gap by developing
conformation-specific nanobodies (NanoNucs) that act as sensors of distinct nucleosome conformations.
NanoNucs will be discovered from a synthetic library containing >2 x 109 distinct nanobodies. We will employ
NanoNucs to gain structural and biophysical insights into nucleosome conformational dynamics and to probe
and perturb the nucleosome conformational code in cells. Specifically, we will: (i) obtain atomic understanding
of nucleosome alternative states by combining NMR, HDX-MS, and cryo-EM; (ii) identify chromatin factors that
sense and leverage nucleosome plasticity; (iii) search for nucleosome conformations that are biological or
pathological biomarkers; and (iv) develop a novel strategy to manipulate nucleosome shapes and chromatin
states in cells. By carrying out this highly ambitious, integrated, and multidisciplinary research program, my lab
will unveil the molecular mechanisms and therapeutical potential of the nucleosome conformational code. I
anticipate that these high-risk, high-reward investigations will reveal new fundamental principles of genome
regulation that shift the long-standing paradigm of rigid histone units and that will broadly impact biomedical
science over the short and long terms. Exploring the structural flexibility of nucleosomes represents an
opportunity to identify novel therapeutic biomarkers and drugs for diseases linked to epigenetics defects, such
as cancer. Ultimately, with critical support from the NIH Director's New Innovator Program, our studies will enrich
our knowledge of the function and physiology of chromatin with atomic-scale biophysical insights into the
chromatin architecture ...

## Key facts

- **NIH application ID:** 10473051
- **Project number:** 1DP2GM149752-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Serena Sanulli
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,416,600
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473051

## Citation

> US National Institutes of Health, RePORTER application 10473051, Harnessing the chromatin conformational code for epigenetic regulation (1DP2GM149752-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10473051. Licensed CC0.

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