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CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor.

ABSTRACT: CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kinase-responsive alternative splicing events, the large majority of which monotonically increase or decrease with increasing CDC-like kinase inhibition. We show that distinct RNA-binding motifs are associated with T3 response in skipped exons. Unexpectedly, we observe dose-dependent conjoined gene transcription, which is associated with motif enrichment in the last and second exons of upstream and downstream partners, respectively. siRNA knockdown of CLK2-associated genes significantly increases conjoined gene formation. Collectively, our results reveal an unexpected role for CDC-like kinase in conjoined gene formation, via regulation of 3'-end processing and associated splicing factors.The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.

SUBMITTER: Funnell T

PROVIDER: S-EPMC5431906 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor.

Funnell Tyler T Tasaki Shinya S Oloumi Arusha A Araki Shinsuke S Kong Esther E Yap Damian D Nakayama Yusuke Y Hughes Christopher S CS Cheng S-W Grace SG Tozaki Hirokazu H Iwatani Misa M Sasaki Satoshi S Ohashi Tomohiro T Miyazaki Tohru T Morishita Nao N Morishita Daisuke D Ogasawara-Shimizu Mari M Ohori Momoko M Nakao Shoichi S Karashima Masatoshi M Sano Masaya M Murai Aiko A Nomura Toshiyuki T Uchiyama Noriko N Kawamoto Tomohiro T Hara Ryujiro R Nakanishi Osamu O Shumansky Karey K Rosner Jamie J Wan Adrian A McKinney Steven S Morin Gregg B GB Nakanishi Atsushi A Shah Sohrab S Toyoshiba Hiroyoshi H Aparicio Samuel S

Nature communications 20170223 1

CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kina ...[more]

PMID: 28232751

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Project description:ImportanceLipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.ObjectiveTo determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.Design, setting, and participantsThis phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands.InterventionsThe single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.Main outcomes and measuresOutcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers.ResultsAmong 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed.ConclusionMuvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes.Trial registrationClinicalTrials.gov Identifier: NCT04472676.

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CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor.

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CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor.

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