Integrative Analysis Reveals Histone Demethylase LSD1/KDM1A Regulates RNA Polymerase II Pausing

Lysine-specific demethylase 1 (LSD1) catalyzes the demethylation at H3K4 and H3K9 and is well- known for its role in decommissioning enhancers during mouse embryonic stem cell (ESC) differentiation. However, its role at gene promoters remains poorly understood in ESCs despite their widespread presence at these sites. Here, we report that LSD1 promotes RNA Polymerase II (RNAPII) pausing, a rate-limiting step in transcription regulation, in ESCs. We found that the knockdown of LSD1 preferentially affects genes with higher RNAPII pausing than those with lower pausing. We show that LSD1 knockdown leads to the global reduction in RNAPII pausing and most significantly on the genes bound by LSD1. Next, we demonstrate that the co-localization of LSD1 and MYC, a factor known to regulate pause-release, is associated with the enrichment of other RNAPII pausing factors. Finally, we found that genes co-occupied by LSD1 and MYC are significantly enriched for housekeeping genes that are involved in metabolic processes and depleted of transcription factors compared to those bound only by LSD1. Our integrative analysis reveals a pleiotropic role of LSD1 in promoting RNAPII pausing and in regulating housekeeping programs besides its known role in regulating cell identity programs. Investigating the role of LSD1/KDM1A in RNA Polymerase II Pausing