Abstract
Lysine-specific demethylase 1 (LSD1) is well-known for its role in decommissioning enhancers during mouse embryonic stem cell (ESC) differentiation. Its role in gene promoters remains poorly understood despite its 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 the knockdown of LSD1 preferentially affects genes with higher RNAPII pausing. Next, we demonstrate that the co-localization sites of LSD1 and MYC, a factor known to regulate pause-release, are enriched for other RNAPII pausing factors. We show that LSD1 and MYC directly interact and MYC recruitment to genes co-regulated with LSD1 is dependent on LSD1 but not vice versa. The co-regulated gene set is significantly enriched for housekeeping processes and depleted of transcription factors compared to those bound by LSD1 alone. Collectively, our integrative analysis reveals a pleiotropic role of LSD1 in promoting RNAPII pausing.