The H3K36me2 writer-reader dependency in H3K27M-DIPG

Area of Science:

• Epigenetics
• Oncology
• Pediatric Neuro-oncology

Background:

• Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brain tumor driven by the Histone H3K27M mutation.
• H3K27M mutation alters the epigenome by inhibiting PRC2 activity and decreasing H3K27me2/3 marks, leading to increased H3K36me2 levels.
• The aberrant elevation of H3K36me2 is a potential therapeutic target in H3K27M-DIPG.

Purpose of the Study:

• To investigate the role of H3K36me2 in H3K27M-DIPG pathogenesis.
• To identify the enzymes responsible for H3K36me2 production (writers) and the proteins that bind to it (readers).
• To explore therapeutic strategies targeting the H3K36me2 pathway.

Main Methods:

• Investigated the role of histone modifying enzymes NSD1 and NSD2 as H3K36me2 writers.
• Identified LEDGF and HDGF2 as the primary readers of H3K36me2.
• Utilized a chemically modified peptide mimicking H3K36me2 to disrupt reader binding and assess therapeutic efficacy.

Main Results:

• NSD1 and NSD2 were confirmed as the key writers of H3K36me2 in H3K27M-DIPG.
• Loss of NSD1/2 function inhibited DIPG cell proliferation and tumorigenesis.
• LEDGF/HDGF2 were identified as crucial readers mediating protumorigenic effects downstream of H3K36me2.
• A peptide-based therapy targeting H3K36me2 specifically inhibited H3K27M-DIPG proliferation by dislodging LEDGF/HDGF2 from chromatin.

Conclusions:

• A functional pathway involving NSD1/2, H3K36me2, and LEDGF/HDGF2 represents an acquired dependency in H3K27M-DIPG.
• Targeting this pathway offers a promising therapeutic strategy for DIPG.