The C-terminal domain of the RNA polymerase (RNAP) II largest subunit (CTD) plays critical roles both in transcription of mRNA precursors and in the processing reactions needed to form mature mRNAs. The CTD undergoes dynamic changes in phosphorylation during the transcription cycle, and this plays a significant role in coordinating its multiple activities. But how these changes themselves are regulated is not well understood. Here we show that the peptidyl-prolyl isomerase Pin1 influences the phosphorylation status of the CTD in vitro by inhibiting the CTD phosphatase FCP1 and stimulating CTD phosphorylation by cdc2/cyclin B. This is reflected in vivo by accumulation of hypophosphorylated RNAP II in pin1 −/− cells, and of a novel hyper-hyperphosphorylated form in cells induced to overexpress Pin1. This hyper-hyperphosphorylated form of RNAP II also accumulates in M-phase cells, in a Pin1-dependent manner, and associates specifically with Pin1. Functionally, we find that Pin1 overexpression specifically inhibits ongoing transcription of mRNA precursors in vivo and both transcription and RNAP II-stimulated pre-mRNA splicing in cell extracts. Pin1 thus plays a significant role in regulating RNAP II CTD structure and function.

. Using inducible Pin1 cell lines, we show that Pin1 overexpression is sufficient to release RNAP II from chromatin, which then accumulates in a hyperphosphorylated form in nuclear speckle-associated structures. In vitro transcription assays show that Pin1 inhibits transcription in nuclear extract, while an inactive Pin1 mutant in fact stimulates it. Several assays indicate that the inhibition largely reflects Pin1 activity during transcription initiation and not elongation, suggesting that Pin1 modulates CTD phosphorylation, and RNAP II activity, during an early stage of the transcription cycle.[Keywords: CTD; CTD phosphorylation; Pin1; prolyl isomerase; RNAP II] Supplemental material is available at http://www.genesdev.org.

Reduced secretion and increased uptake of ApoB-containing lipoproteins may contribute to the low LDL-C observed in mice and humans with genetic ANGPTL3 deficiency.

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Previous studies have revealed the critical roles of the N6-methyladenosine (m6A) modification of long non-coding RNAs (lncRNAs) in cancers, but the relationship between the oncogenic role of the lncRNA THOR (a representative of cancer/testis lncRNAs) and m6A modification remains unclear. Here, we show that the internal m6A modification of the lncRNA THOR via an m6A-reader-dependent modality regulates the proliferation of cancer cells. Our findings demonstrated that the loss of the lncRNA THOR inhibits the proliferation, migration, and invasion of cancer cells in vitro and in vivo. In addition, m6A is highly enriched on lncRNA THOR transcripts, which contain GA (m6A) CA, GG (m6A) CU, and UG (m6A) CU sequence motifs. RIP-qRT-PCR and RNA pull-down assay results revealed that the specific m6A readers YTHDF1 and YTHDF2 can read the m6A motifs and regulate the stability of the lncRNA THOR (stabilization and decay). These m6A-dependent RNA-protein interactions can maintain the oncogenic role of the lncRNA THOR. Collectively, these findings highlight the critical role of the m6A modification in oncogenic lncRNA THOR and reveal a novel long non-coding RNA regulatory mechanism, providing a new way to explore RNA epigenetic regulatory patterns in the future. Recently, the new field of "RNA epigenetics" has been booming 14,15 , and N6-methyladenosine (m6A) has been identified as a post-transcriptional regulatory mark in multiple RNA species, including messenger RNAs (mRNAs) 1,2,16 , transfer RNAs (tRNAs) 3,4,17-20 , ribosomal RNAs (rRNAs) 21 , small nuclear RNA 22 , small non-coding RNAs (sncRNAs) 23 , and lncRNAs 16,24. It has been reported that the m6A RNA modification is conferred by methyltransferases (writers), such as methyltransferaselike 3 (METTL3), forming the catalytic core of the m6A methyltransferase complex 25-28. In addition, the biological function of m6A is mediated through the recognition of the m6A site by m6A "readers" 1,29,30 , such as the YT521-B homology (YTH) family, including YTH domain