Post-Transcriptional Regulation of Homeostatic, Stressed, and Malignant Stem Cells

Abstract

Cellular identity is not driven by differences in genomic content but rather by epigenomic, transcriptomic, and proteomic heterogeneity. Although regulation of the epigenome plays a key role in shaping stem cell hierarchies, differential expression of transcripts only partially explains protein abundance. The epitranscriptome, translational control, and protein degradation have emerged as fundamental regulators of proteome complexity that regulate stem cell identity and function. Here, we discuss how post-transcriptional mechanisms enable stem cell homeostasis and responsiveness to developmental cues and environmental stressors by rapidly shaping the content of their proteome and how these processes are disrupted in pre-malignant and malignant states.

Figure 1.. Post-transcriptional mechanisms influence proteome content.

Proteome content can be regulated by RNA processing, ribosome biogenesis, signaling pathways and protein degradation. RNA splicing can produce mRNAs that code for distinct protein isoforms, introduce premature stop codons, or cause UTR variation that alters translational efficiency. mRNA methylation can alter transcript stability, localization and translational efficiency. Methylation and pseudouridylation of rRNA and tRNA can impact ribosome biogenesis, polysome assembly, translation fidelity and tRNA stability. RNA editing can alter miRNA biogenesis and alter mRNA coding or UTR sequence to alter translational efficiency. The mTOR signaling pathway can promote protein synthesis by enhancing the translation of ribosomal protein mRNAs via phosphorylation of Larp1, ribosome biogenesis via phosphorylation and activation of S6K, and translation initiation via phosphorylation and inhibition of 4E-BPs. The ubiquitin-proteasome system is a major cellular degradation system that contributes to maintaining proteostasis in stem cells by regulating both the content and quality of the proteome through the normal turnover of proteins and the degradation of misfolded proteins.

Figure 2.. Post-transcriptional regulation of stem cell identity under conditions of stress.

In response to proteotoxic insults, the cell mounts adaptive responses to maintain protein quality control. These stress response pathways also regulate stem cells. (A) The heat shock response induces ESC differentiation, protects ESCs from cellular stress, promotes myoblast differentiation, and supports erythropoiesis. (B) Activation of the UPR^MT by nicotinamide riboside delays neural stem cell and melanocyte stem cell senescence, while dysregulation of the UPR^MT also impairs hematopoietic and intestinal stem cell stemness and proliferation. (C) Post-transcriptional mechanisms of gene regulation including RNA methylation and protein synthesis can regulate the cellular response to oxidative stress. However, the precise nature of this relationship and its influence on stem cells is largely unknown. (D) The effects of UPR^ER activation on stem cells are tissue- and context-specific. Activation of the PERK branch regulates muscle satellite cell differentiation during homeostasis, but results in a loss of intestinal stem cell self-renewal during stress. Induction of ATF6 and IRE1 through pharmacological means supports mesodermal specification of ESCs and enhances the reprogramming efficiency of somatic stem cells. Activation of the PERK branch during homeostasis promotes the engraftment of HSCs, and during conditions of moderate stress promotes their survival. The IRE1 pathway provides a protective effect on HSCs experiencing stress. However, extreme stress induces HSC apoptosis.