# Structure and Mechanism of the SET1/COMPASS H3K4 Methyltransferase Complex

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $375,083

## Abstract

Project Summary
The post-translational modification of histone H3 lysine 4 (H3K4) by methyl groups is an evolutionarily conserved
epigenetic mark that is generally associated with transcription activation in all eukaryotic cells. Early studies of
the yeast model system, S. cerevisiae, have not only identified the prototype of the SET1/MLL family of
methyltransferases as the enzyme responsible for H3K4 mono-, di-, and trimethylation, but also revealed a yeast
Set1-centric protein complex, known as COMPASS, that stabilizes and confers catalytic activity to the enzyme.
The SET1/MLL family of H3K4 methyltransferases has undergone a significant expansion in animals. Mammals
have evolved a total of six distinct and functionally non-redundant family members, each of which also functions
within a COMPASS or COMPASS-like complex. Remarkably, recent studies have shown that mutations or
dysregulation of the six human SET1/MLL methyltransferases are associated with a spectrum of mental
illnesses, including schizophrenia, autism, and intellectual disability disorders. Malfunctions of some of these
family members are further linked to other human diseases such as mixed lineage leukemia and congenital heart
disease. Despite their important biological roles and their high relevance to human health, a molecular and
mechanistic understanding of the SET1/MLL H3K4 methyltransferases is largely lacking due to the large sizes
of most SET1/MLL enzymes and the complexity associated with their assemblies and regulation. To date, most
structural and biochemical studies have been focused on single domains and small fragments of the yeast and
human SET1/MLL enzymes and COMPASS subunits. Many questions, such as how the SET1/MLL enzymes
bind and become regulated by four common catalytic module subunits, namely RBBP5/Swd1, WDR5/Swd3,
ASH2L/Bre2, and DPY30/Sdc1 (human/yeast ortholog), how the resulting complexes recognize H3K4 in the
context of nucleosome and differentially catalyze mono- vs. multi-H3K4 methylation, and how the activities of
COMPASS and COMPASS-like complexes are regulated by upstream signals such as H2B mono-ubiquitination
remain unclear. Using a combination of structural, chemical and biochemical approaches, as well as yeast cell-
based functional assays, we propose to dissect the structure and function relationship of the yeast Set1
COMPASS complex as a model system and extend this work to the clinically relevant human SET1/MLL
complexes. Our proposed studies hold the promise to establish the missing framework for understanding the
structural basis of the SET1/MLL H3K4 methyltransferase function and regulation in eukaryotic biology and
unmasking the molecular mechanisms of various human diseases associated with their malfunction.

## Key facts

- **NIH application ID:** 10906012
- **Project number:** 5R01HD097408-05
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Champak Chatterjee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $375,083
- **Award type:** 5
- **Project period:** 2020-09-08 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906012

## Citation

> US National Institutes of Health, RePORTER application 10906012, Structure and Mechanism of the SET1/COMPASS H3K4 Methyltransferase Complex (5R01HD097408-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10906012. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*