Epigenetic and transcriptional regulation of dendritic cell development and anti-tumor function by HDAC1 (CUT&RUN)

DC progenitors adapt their transcriptional program during development generating different subsets. How chromatin modifications modulate these processes is unclear. Here we investigate the impact of histone deacetylation on DCs by genetically deleting HDAC1 or HDAC2 in hematopoietic progenitors and CD11c-expressing cells. While HDAC2 isn’t critical for DC development, HDAC1 deletion impairs pro- and mature pDC generation and affects ESAM+cDC2 differentiation from tDC and pre-cDC2, whereas cDC1s are unchanged. HDAC1 knock-down in human hematopoietic cells also impairs cDC2 development highlighting its crucial role across species. Multi-omics analyses reveal that HDAC1 controls expression, chromatin accessibility and histone-acetylation of the transcription factors IRF4, IRF8 and SPIB required for efficient development of cDC2 subsets. Without HDAC1, DCs switch immunologically enhancing tumor surveillance through increased cDC1 maturation and IL-12 production driving Th1-mediated immunity and CD8+T-cell recruitment. Our study reveals the importance of histone-acetylation in DC development and anti-tumor immunity suggesting DC-targeted therapeutic strategies for immuno-oncology.