# Role of novel histone modifications and variants in transcriptional regulation

> **NIH NIH R35** · EMORY UNIVERSITY · 2024 · $385,206

## Abstract

PROJECT SUMMARY
Posttranslational modification (PTM) of nucleosome-associated histone proteins, along with histone variant
incorporation, influences transcriptional competence and their dysregulation has been identified in numerous
pathological states. Histone H3 N-terminal acetylation, methylation, and phosphorylation are common PTMs; the
precise combination of these PTMs can modulate chromatin architecture and genome organization, leading to
changes in gene expression. Despite extensive efforts to characterize H3 PTMs and H3 variants, their
mechanistic and functional interplay, and their ability to influence biological output, it remains unclear how
histones and many histone PTMs integrate cues from upstream signaling cascades to regulate gene expression.
The overarching objective for my laboratory is to define mechanisms that regulate histone PTM patterns and
unmask how they influence transcriptional output. Over the next five years, we propose a combinatorial approach
leveraging genetic, molecular, cellular, biochemical and computational methods to define novel mechanisms by
which a poorly understood histone H3 PTM, H3 threonine 45 phosphorylation (pH3T45), relays cellular signals
from upstream kinases to impact gene expression, and leverage this approach to delineate how novel pathogenic
histone H3 variants dysregulate the epigenome to alter cellular function. Our preliminary data suggest that H3T45
phosphorylation status (1) modulates H3K4 methylation by directing specific H3K4-modifying complexes to
chromatin; (2) disrupts H3K36me3 via competing histone acetylation/deacetylation; (3) regulates RNA
processing through differential association with splicing factors and the RNA exosome complex. We will dissect
how H3K4-methyltransferase complexes differ in structure, function, and biological output when associated with
pH3T45 or unmodified H3T45. We will delineate how pH3T45 impacts the dynamics of H3K36 acetylation and
H3K36 methylation in the context of DNA repair. We will then define how pH3T45 governs the production of
mature RNA by examining the role of unmodified H3T45 and pH3T45 throughout RNA processing. Lastly, we
have identified a series of cancer-associated H3 variants in which an amino acid is changed to a lysine, termed
“H3 X to K” variants. Our preliminary data demonstrates that H3 X to K variants dysregulate proximal H3 PTMs
to uniquely modulate gene expression. We will leverage our experience studying pH3T45 to mechanistically
define how H3 X to K variants reprogram the epigenome to produce transcriptional and functional cellular
changes. This research will address the regulation and effects of histone PTM patterns and H3 variant
expression, which will inform our view of how H3 PTMs and variant expression underlies human disease.

## Key facts

- **NIH application ID:** 10891533
- **Project number:** 5R35GM150587-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jennifer Marie Spangle
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,206
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891533

## Citation

> US National Institutes of Health, RePORTER application 10891533, Role of novel histone modifications and variants in transcriptional regulation (5R35GM150587-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10891533. Licensed CC0.

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