Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis

• Published in: Nature immunology Vol. 20; no. 1; pp. 86 - 96
• Main Authors: Hatzi, Katerina, Geng, Huimin, Doane, Ashley S., Meydan, Cem, LaRiviere, Reed, Cardenas, Mariano, Duy, Cihangir, Shen, Hao, Vidal, Maria Nieves Calvo, Baslan, Timour, Mohammad, Helai P., Kruger, Ryan G., Shaknovich, Rita, Haberman, Ann M., Inghirami, Giorgio, Lowe, Scott W., Melnick, Ari M.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2019; Nature Publishing Group
• Subjects: 631/250/1619/40; 631/250/2152/2153/1982; 631/250/2502/2170; 631/67/1990/291; Animals; B cells; B-Lymphocytes - physiology; Bcl-6 protein; Biomedical and Life Sciences; Biomedicine; Carcinogenesis; Clonal deletion; CRISPR; CRISPR-Cas Systems; Dependence; Development and progression; DNA, Intergenic - genetics; Enhancers; Gene expression; Genes; Genetic aspects; Germinal Center - immunology; Germinal Center - pathology; Germinal centers; Histone Demethylases - genetics; Histone Demethylases - metabolism; Hyperplasia; Immune response; Immune response (humoral); Immunological Synapses - genetics; Immunology; Infectious Diseases; Introns - genetics; Lymphocytes B; Lymphoma; Lymphoma - genetics; Lymphoma - metabolism; Lymphomas; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-bcl-6 - genetics; Proto-Oncogene Proteins c-bcl-6 - metabolism; Transcription; Transcription (Genetics); Transcription factors; Tumors
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-018-0273-1

Germinal center (GC) B cells feature repression of many gene enhancers to establish their characteristic transcriptome. Here we show that conditional deletion of Lsd1 in GCs significantly impaired GC formation, associated with failure to repress immune synapse genes linked to GC exit, which are also direct targets of the transcriptional repressor BCL6. We found that BCL6 directly binds LSD1 and recruits it primarily to intergenic and intronic enhancers. Conditional deletion of Lsd1 suppressed GC hyperplasia caused by constitutive expression of BCL6 and significantly delayed BCL6-driven lymphomagenesis. Administration of catalytic inhibitors of LSD1 had little effect on GC formation or GC-derived lymphoma cells. Using a CRISPR-Cas9 domain screen, we found instead that the LSD1 Tower domain was critical for dependence on LSD1 in GC-derived B cells. These results indicate an essential role for LSD1 in the humoral immune response, where it modulates enhancer function by forming repression complexes with BCL6. Germinal center B cells undergo reiterative rounds of proliferation and selection. Melnick and colleagues show that the histone demethylase LSD1 is necessary for this reiterative process via its interactions with the transcription factor BCL6.