# Histone crotonylation as a novel regulator of learning and memory > **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2024 · $73,828 ## Abstract PROJECT SUMMARY The goal of this proposal is to define how novel post-translational modifications (PTMs) on histones are regulated by neuronal activity and to test their role in learning and memory. In the brain, gene expression changes facilitate essential neural processes such as memory formation. PTMs like acetylation are known to regulate these processes. This proposal focuses on crotonylation, a recently discovered histone PTM in the acyl family. Histone crotonylation impacts gene expression in multiple cell types, generally upregulating expression. While it is not yet clear whether histone crotonylation also regulates neuronal gene expression and function, there is evidence showing that it can influence the development of psychological disorders as well as neurodevelopmental disorders. For instance, several acetyl-lysine readers have a specific preference for crotonyl-lysine over acetyl-lysine, and mutations in the genes encoding these proteins cause neurodevelopmental syndromes characterized by developmental delay and intellectual disability. Thus, understanding the regulation and function of histone crotonylation in the brain has the potential to illuminate mechanisms by which epigenetic regulators influence disease. To date, the study of crotonylation has been hindered by a lack of specificity in the reagents that detect crotonylation and by a lack of tools to specifically manipulate it in physiological contexts. This proposal will leverage novel tools including a crotonyl-specific probe and crotonyl-specific enzymes to gain an understanding of how histone crotonylation is regulated by neural activity and to discern how it functions in the regulation of gene expression and in learning and memory. This proposal presents two integrated aims to test the overarching hypothesis that histone crotonylation enhances transcription of activity-dependent genes to promote learning and memory formation. In Aim 1, we will use primary neuronal culture systems to study how neuronal activation affects histone crotonylation over time. The novel approaches used in this Aim will map the broad, dynamic changes in crotonylation induced by neuronal activation while also quantifying site-specific histone residues with altered crotonylation status during neuronal activation. In Aim 2, we will utilize viral vectors to express mutant forms of histone acyl- and deacyl-transferase enzymes that specifically deposit or remove crotonylation. We will use these enzymes in neuronal cultures to determine how changes in histone crotonylation affect gene expression in response to activating stimuli. We will also test whether crotonylation plays a functional role in learning and memory in mice by injecting lentiviruses expressing crotonyl-specific acyltransferase enzymes under the control of a neuron-specific promoter to increase or decrease crotonylation. We will then evaluate the effects of these manipulations on memory through behavioral testing. Ultimately this proposal... ## Key facts - **NIH application ID:** 10996441 - **Project number:** 1F32MH138117-01 - **Recipient organization:** UNIVERSITY OF PENNSYLVANIA - **Principal Investigator:** Jenna Rose Petronglo - **Activity code:** F32 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $73,828 - **Award type:** 1 - **Project period:** 2024-08-01 → 2027-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10996441 ## Citation > US National Institutes of Health, RePORTER application 10996441, Histone crotonylation as a novel regulator of learning and memory (1F32MH138117-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10996441. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*