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

RNA polymerase II (RNAPII) pausing at gene promoters is a rate-limiting step in transcription regulation. Previous studies have elucidated the coordinated actions of pausing and releasing factors that collectively modulate RNAPII pausing. In general, the involvement of chromatin remodellers in RNAPII pausing has not been well documented. Whilst LSD1 is well-known for its role in decommissioning enhancers during ESC differentiation, its role at the promoters of genes remains poorly understood despite their widespread presence at these sites. Here, we report that LSD1 is associated with RNAPII pausing at the promoter-proximal region of genes in mouse embryonic stem cells (ESCs). We demonstrate that the knockdown of LSD1 preferentially affects genes with higher RNAPII pausing than those with lower pausing and, importantly, show 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 compared to their independent counterparts. Moreover, we found that genes co-occupied by LSD1 and MYC are significantly enriched for housekeeping genes that are involved in metabolic processes and globally depleted of transcription factors compared to those bound only by LSD1. These findings reveal a pleiotropic role of LSD1 in regulating housekeeping program besides its previously known role in regulating cell identity programs. Our integrative analysis presents evidence for a previously unanticipated role of LSD1 in RNAPII pausing through its association with pause release factors in modulating cell-type specific and cell-type invariant genes.