Maf1 cooperates with progesterone receptor to repress RNA polymerase III transcription of select tRNAs

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Abstract
Progesterone receptors (PRs) can regulate transcription by RNA polymerase III (Pol III), which transcribes small non-coding RNAs, including all transfer RNAs (tRNAs). We previously demonstrated that PR is associated with the Pol III complex at tRNA genes and that progestins downregulate tRNA transcripts in breast tumor models. To define this mechanism, we investigated the interplay between PR, the Pol III repressor Maf1, and TFIIIB, a core transcription component. ChIP-seq was performed for PR, the Pol III subunits POLR3A, POLR3C, and POLR3G, the TFIIIB component Brf1, and Maf1 in breast cancer cells with or without progestin treatment. With progestin treatment, PR localized to ∼50% of POLR3A-occupied tRNA genes, with Maf1 co-recruited at many of these sites. Progestin treatment did not significantly alter the number of tRNA genes occupied by Pol III subunits or Brf1; however, Brf1 occupancy was stabilized. Progestins downregulated nascent transcription of one-third of tRNA genes; this repression was attenuated by Maf1 knockdown, indicating that Maf1 is required. The PR and Maf1 interaction was also detected by co-immunoprecipitation in a progestin-dependent manner. Overall, these findings demonstrate a ligand-dependent PR-mediated repression of tRNA transcription that involves Maf1.
Funding Information
  • National Institutes of Health (R01 GM146373, R35 GM144336)
  • American Cancer Society (IRG 16-184-56)
  • Breast Cancer Research Foundation (BCRF-23-144)

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