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Enhanced phase separation of BRD4S derived from CDK12 inactivation-induced IPA drives cancer metastasis

ABSTRACT: CDK12 gene is frequently deleted/mutated in human cancers and CDK12 loss associates with intronic polyadenylation (IPA). Here, we show that CDK12 deficiency induces IPA usage in BRD4 gene locus and expression of the BRD4 short form (BRD4S). Different from the full-length BRD4 (BRD4L) that possesses a C-terminal intrinsically disordered region (IDR), surprisingly, BRD4S has a greater capacity to form phase separation in a manner dependent on oligomerization mediated by a base-interacting structural domain (BID). Through CUT&Tag profiling, we identify BRD4S specifically binds to the promoters of and transcriptionally upregulates TGF-β signaling genes including TGFB2 and LTBP1. Our study identifies IPA usage at the BRD4 gene locus as a previously unrecognized mechanism responsible for BRD4S genesis. Our findings also reveal an essential role of BRD4S condensation formation and a unique ability of BRD4S to turn on TGF-β signaling gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293829 | GEO | 2025/11/13

REPOSITORIES: GEO

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Project description:Most available CRC cell lines have lost their TGF-beta response through the acquisition of mutations either in TGF-beta type II receptor (TGFBR2) or the intracellular mediator SMAD4 (Reviewed in Markowitz et al. 2002). To study the effect of TGF-beta in CRC epithelial cells, we restored wild-type TGFBR2 expression in the CRC cell line LS174T (LS). Ls174T cells are mutant for beta-catenin and therefore exhibit constitutive Wnt activity, which results in the expression of a genetic profile similar to that of intestinal epithelial progenitor cells (van de Wetering, Sancho et al. 2002). They thus reflect tumor cells at the initial stages of tumorogenesis. In addition, Ls174T cells bear mutations in the TGF-beta receptor II (TGFBR2) sequence at the BATRII locus (Grady and Markowitz 2002). This mutation gives rise to a non-functional truncated form of the receptor lacking the transmembrane domain and the serine-threonine kinase domain (Parsons, Myeroff et al. 1995). We generated inducible clones of Ls174T cells, where the expression of TGFBR2 could be controlled at will by the presence or absence of doxycycline (LSTGFBR2 cell line). Re-expression of wild-type receptor in Ls174T cells (LSTGFBR2) restored TGF-beta signalling resulting in strong phosphorylation of SMADs and activation of SMAD-binding reporter activity. Functionally, TGF-beta signalling in LSTGFBR2 resulted in a strong cytostatic response. By genome wide expression profiling using microarrays we investigated genes regulated by TGF-beta in this cell line. LsTGFBR2 inducible cells were generated by the Invitrogen T-Rex system following manufacturers instructions. LSTGFBR2 were seeded at 60% confluence in the presence or absence of Doxycycline and treated with TGF-M-NM-21 for 16 hours. Gene expression profiles were measured in duplicate using HG-U133 plus 2.0. We used RMA background correction, quantile normalization and RMA summarization (Gautier et al., 2004). A TGF-M-NM-2 response signature was obtained by selecting genes with limma P-value < 0.05 and at least two fold up-regulation in TGF-M-NM-2 treated LSTGFBR2 cells.

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Enhanced phase separation of BRD4S derived from CDK12 inactivation-induced IPA drives cancer metastasis

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