CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue

Abstract

Summary Somatic progenitors sustain tissue self-renewal while suppressing premature differentiation. Protein arginine methyltransferases (PRMTs) impact many processes, however, their role in progenitor function is incompletely understood. PRMT1 was found to be the most highly expressed PRMT in epidermal progenitors and the most downregulated PRMT during differentiation. In targeted mouse knockouts and in long-term regenerated human mosaic epidermis in vivo, epidermal PRMT1 loss abolished progenitor self-renewal and led to premature differentiation. Mass spectrometry of the PRMT1 protein interactome identified the CSNK1a1 kinase, which also proved essential for progenitor maintenance. CSNK1a1 directly bound and phosphorylated PRMT1 to control its genomic targeting to PRMT1-sustained proliferation genes as well as PRMT1-suppressed differentiation genes. Among the latter were GRHL3, whose de-repression was required for the premature differentiation seen with PRMT1 and CSNK1a1 loss. Maintenance of the progenitors thus requires cooperation by PRMT1 and CSNK1a1 to sustain proliferation gene expression and suppress premature differentiation driven by GRHL3.

PRMT1 Is Recruited via DNA-PK to Chromatin Where It Sustains the Senescence-Associated Secretory Phenotype in Response to Cisplatin

“…Different scenarios supporting this model remain to be assessed: one possibility is that DNA-PK modulates the substrate affinity of PRMT1 through phosphorylation, in line with a previous study demonstrating that PRMT1 phosphorylation at tyrosine 291 can regulate the differential affinity of the enzyme toward its own substrates (Rust et al, 2014). Alternatively, PRMT1 phosphorylation could directly favor PRMT1 accumulation on chromatin, as it was recently shown for PRMT1 phosphorylation mediated by CSNK1a1 (Bao et al, 2017).…”

PRMT1 promotes neuroblastoma cell survival through ATF5

“…These findings lead us to hypothesize that PRMT1 may activate ATF5 transcription through modulating H4R3me2a mark. First, to assess whether PRMT1 binds to the ATF5 locus, we retrieved our recent ChIPseq results in human keratinocytes expressing HA-PRMT1 13 . By using two different antibodies, we observed PRMT1 peaks that were enriched at the ATF5 gene locus (Fig.…”

Casein kinase 1α: biological mechanisms and theranostic potential

“…CK1α suppression leads to Wnt activation and transforming growth factor β/mothers against decapentaplegic homolog 2 inhibition, resulting in the conversion of epiblast stem cells into embryonic stem cells (ESCs) [ 190 ] and promoting the establishment and maintenance of the pluripotency network [ 191 ]. CK1α directly phosphorylates protein arginine methyltransferase 1 (PRMT1) (mainly at Ser284/Thr285/Ser286/289) to suppress grainyhead-like transcription factor 3 (GRHL3)-mediated terminal differentiation and maintain somatic tissue in a state of self-renewal [ 192 ]. Additionally, competitive bone marrow repopulation assays have demonstrated that CK1α is essential for long-term HSCs function [ 193 ].…”