RNA-seq analysis of WT, SREBP knockout and SREBP2 knockout HeLa cells and liver samples of WT and SREBP2 (F167A) knockin mice

The transcription factor SREBP2, plays a specific and non-redundant role in cholesterol metabolism, autophagy of lipid droplets and apoptosis regulation. Under cholesterol-depletion condition, nuclear SREBP2 (nSREBP2) is released after proteolytic cleavage, enters nucleus and activates cholesterogenic genes expression. Here, we report that the nSREBP2 forms discrete nuclear condensates through its N-terminal intrinsically disordered region (IDR) and works together with transcription coactivators BRD4 and p300, partly on super-enhancers, for the transcriptional activation of SREBP2 target genes. The substitution of a critical and conserved phenylalanine (F) to alanine (A) within the IDR abolished the formation of nSREBP2 condensates. Conversely, the condensate formation and efficient transcription activation were rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the F to A substitution in mice compromised the feeding-induced nSREBP2 activity and lowered the cholesterol levels. Furthermore, a SNP of SREBF2 in humans leading to single amino acid change, P183S, showed less nuclear condensate formation and lower transcriptional activity, underscoring the physiological relevance of nSREBP2 condensates. Together, this study reveals that nuclear condensates driven by the N terminal IDR of nSREBP2 facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.