# Histone Arginine Demethylation through Cleavage

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2023 · $426,167

## Abstract

In higher eukaryotes, RNA Polymerase II (Pol II) pausing is a critical regulation mechanism controlling
development, differentiation, proliferation, immune response, and all variety of cell function. Dysfunction of the
regulation will lead to developmental defects, irregular immune responses, cancers, accelerating aging, and
different diseases.
 A major portion (over ~30%) of genes in higher eukaryotes (in human and mice, not in yeast) are
regulated by Pol II pausing. The release of paused Pol II at the +1 nucleosome is thought to require
phosphorylation of C-terminal domain (CTD) of Pol II, NELF, and DSIF by CDK9. However, the precise role of
phosphorylation of CTD of Pol II by CDK9 in Pol II pausing regulation is not well understood, nor if other
mechanisms for pause release also contribute. In this proposal, we are proposing an innovative new idea that,
if correct, will be paradigm changing. That is that in addition to the known mechanisms for pause release,
JMJD5 is recruited by Pol II with Ser2 phosphorylation of CTD generated by CDK9 to carry out its proteolytic
function on arginine methylated histone tails to generate “Tailless Nucleosomes” at +1 from TSS for paused
Pol II to overcome.
 The phenomenon of clipping of histone tails and high turnover rate of histone was reported more than
three decades ago; however, this process is still poorly understood in part due to the lack of identified enzymes
responsible for the clipping process. Despite the confirmed importance of methylation of histone arginines in
transcriptional regulation, the exact function of this modification is not very well understood. At the same time,
the identities of histone arginine demethylases have remained elusive, though some candidates have been
assigned. We propose that arginine methylation on nucleosomes at +1 from TSS represent a marker for genes
regulated by paused Pol II. Furthermore, a group of Jumonji C (JmjC) domain containing protein family could
specifically clip histone tails with methylated arginines on these nucleosomes.
 In the past two decades, we and other researchers have revealed that the JmjC domain family members
have diverse enzymatic activities. Overall, these functions are related to the JmjC/cupin-like dioxygenase
domains that are the hallmark of this protein family. We now have growing evidence that a subgroup of JmjC
domain family, including JMJD5, JMJD7, and possibly others, may remove histone tails with methylated
arginines through novel endopeptidase and aminopeptidase activities. We claimed that there exists a third
protease family in life science with both endopeptidase and exopeptidase activities. Our preliminary functional
data strongly suggests that JMJD5 and JMJD7 specifically recognize methylated arginines and make cleavages
in the context of histone tails. Our structural analysis of JMJD5 and JMJD7 with and without substrates revealed
unique features and surface charge distribution properties of these proteins that may account f...

## Key facts

- **NIH application ID:** 10693175
- **Project number:** 5R01GM135421-04
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** GONGYI ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $426,167
- **Award type:** 5
- **Project period:** 2020-09-08 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693175

## Citation

> US National Institutes of Health, RePORTER application 10693175, Histone Arginine Demethylation through Cleavage (5R01GM135421-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10693175. Licensed CC0.

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