Histone methyltransferase DOT1L differentially affects the development of dendritic cell subsets

Area of Science:

• Immunology
• Epigenetics
• Cell Biology

Background:

• Dendritic cells (DCs) are crucial for orchestrating immune responses.
• While transcription factors controlling DC development are known, epigenetic regulation remains less understood.
• DOT1L is identified as a significant epigenetic regulator in immune cells.

Purpose of the Study:

• To investigate the role of DOT1L-mediated histone H3K79 methylation in canonical DC subsets.
• To elucidate the impact of DOT1L on DC development, function, and gene expression.
• To understand the mechanistic link between DOT1L's methyltransferase activity and its effects on DCs.

Main Methods:

• Mapping DOT1L-mediated H3K79 methylation in DC subsets.
• In vivo and in vitro deletion of the Dot1l gene in myeloid progenitors.
• Analysis of DC subset populations, IFNα production, and antigen presentation pathways.
• Transcriptome analysis of Dot1l-knockout (KO) DC subsets.

Main Results:

• DOT1L regulates both common and DC subset-specific genes.
• Dot1l deletion decreased myeloid progenitors and increased cDC2s, while cDC1s were unaffected.
• Loss of Dot1l in vitro resulted in fewer plasmacytoid DCs (pDCs) and reduced IFNα production.
• Antigen presentation pathways were enriched in Dot1l-KO DCs, with increased MHC class II on pDCs.

Conclusions:

• DOT1L plays a differential role in the development of canonical DC subsets.
• DOT1L activity is essential for pDC development and function.
• DOT1L suppresses antigen presentation pathways in DCs, impacting immune regulation.