Abstract
In self-renewing somatic tissue such as skin epidermis, terminal differentiation genes must be suppressed in progenitors to sustain regenerative capacity. Here we show that hundreds of intronic polyadenylation (IpA) sites are differentially used during keratinocyte differentiation, which is accompanied by downregulation of the Cleavage and Polyadenylation Specificity Factor (CPSF) complex. Sustained CPSF expression in undifferentiated keratinocytes requires the contribution from the transcription factor MYC. In keratinocytes cultured in undifferentiation condition, CSPF knockdown induces premature differentiation and partially affects dynamically used IpA sites. These sites include an IpA site located in the first intron of the differentiation activator GRHL3. CRISPR knockout of GRHL3 IpA increased full-length GRHL3 mRNA expression. Using a targeted genetic screen, we identify that HNRNPA3 interacts with CPSF and enhances GRHL3 IpA. Our data suggest a model where the interaction between CPSF and RNA-binding proteins, such as HNRNPA3, promotes site-specific IpA and suppresses premature differentiation in progenitors.
Highlights
In self-renewing somatic tissue such as skin epidermis, terminal differentiation genes must be suppressed in progenitors to sustain regenerative capacity
Among all these PolyA sites, 2739 of these sites are located in intronic regions (Supplementary Fig. 1b), 17% of which overlaps with the intronic polyadenylation (IpA) sites recently identified in the immune system[24] (Supplementary Fig. 1c, d), highlighting the specificity of IpA events occurring in distinct tissue types
We found that human keratinocyte differentiation involves differential usage of intronic polyadenylation sites
Summary
In self-renewing somatic tissue such as skin epidermis, terminal differentiation genes must be suppressed in progenitors to sustain regenerative capacity. Self-renewing somatic tissue, such as epithelium, undergoes continuous turnover to compensate for wear and tear In this dynamic regeneration process, terminal differentiation is essential for fulfilling the specialized tissue function; terminal differentiation genes must be suppressed in tissue progenitors to sustain their regenerative capacity[1,2]. Several distinct regulatory mechanisms, utilized by the progenitors to repress GRHL3, have been identified recently These include PRMT1 binding at its promoter to influence its transcription, as well as EXOSC9 degrading mRNA post-transcriptionally[2,10]. In addition to the roles of transcription activators, epigenetic and post-transcriptional regulators as well as non-coding RNAs are involved in regulating epidermal differentiation[1,6,11,12,13,14,15,16,17,18] These findings highlight the coexistence of multiple gene regulatory mechanisms, at distinct steps of gene expression, to fine-tune the overall abundance of gene products. How distinct IpA sites are being used in specific biological processes still remains unclear
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