# Potential Role of Compass H3K4 Methyltransferase Complexes in Environmental Circadian-Alignment

> **NIH NIH R16** · MOREHOUSE SCHOOL OF MEDICINE · 2024 · $177,500

## Abstract

Summary/Abstract
 Environmental-Circadian Disruption such as shiftwork and Jetlag imposes major risk on
human health in the U.S. and abroad. It increases the risk of many metabolic and cardiovascular
disorders and cancers and effects over 16% of the U.S. workforce. Yet, the molecular
underpinnings of this process remain unclear.
 In a proteomic analysis of proteins interacting with Cry1, we identified 10 components of
COMPASS complexes. These enzymatic complexes regulate gene transcription by catalyzing
the addition of methyl groups to lysine 4 of histone 3 (H3K4mes) of local chromatin. Interestingly,
these chromatin marks respond to environmental circadian entrainment information such as
light, temperature or nutrients. They also happen in a circadian rhythmic manner and modulate
DNA methylation, a determinant of gene transcription and disease development. Furthermore,
functional perturbations of various COMPASS components were also implicated in pathological
conditions associated with disharmony of environmental and circadian cycles such as breast
cancer and obesity. We thus hypothesize that COMPASS complexes play a key role in
environmental-circadian alignment. Under environmental-circadian alignment condition,
COMPASS complexes are recruited by Cry1 to rhythmically methylate local H3K4s, which prevent
recruitment of DNA methyltransferases resulting in perturbations of DNA methylation and
expression of core clock gene(s). This methylation cascade modulates the circadian pattern of
gene expression, ensuring alignment of the circadian system with daily environmental cycles. The
methylation cascade fails to initiate when internal circadian system mis-aligns with external
environmental cycles, leading to perturbation of the homeostatic state of cells and development
of disorders. We will investigate this hypothesis by pursuing the following initial aims: 1: To
characterize circadian Cry1::COMPASS interaction; Aim 2: To investigate the role of COMPASS
complexes in methylation of core clock genes; Aim 3: To study the effects of environmental-
circadian disruption on COMPASS function.
 The results of this project might unveil the molecular mechanism of a fundamental biological
process: synchronization of daily internal physiological rhythms with external environmental cycles.
They might also illuminate the nuts and bolts of disorders associated with shiftwork.

## Key facts

- **NIH application ID:** 10875599
- **Project number:** 5R16GM146703-03
- **Recipient organization:** MOREHOUSE SCHOOL OF MEDICINE
- **Principal Investigator:** Hao Duong
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $177,500
- **Award type:** 5
- **Project period:** 2022-07-22 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875599

## Citation

> US National Institutes of Health, RePORTER application 10875599, Potential Role of Compass H3K4 Methyltransferase Complexes in Environmental Circadian-Alignment (5R16GM146703-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10875599. Licensed CC0.

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