DDX6 Orchestrates Mammalian Progenitor Function through the mRNA Degradation and Translation Pathways

Abstract

SUMMARY In adult tissues, stem and progenitor cells must balance proliferation and differentiation to maintain homeostasis. How this is done is unclear. Here, we show that the DEAD box RNA helicase, DDX6 is necessary for maintaining adult progenitor cell function. DDX6 loss results in premature differentiation and decreased proliferation of epidermal progenitor cells. To maintain self-renewal, DDX6 associates with YBX1 to bind the stem loops found in the 3′ untranslated regions (UTRs) of regulators of proliferation/self-renewal (CDK1, EZH2) and recruit them to EIF4E to facilitate their translation. To prevent premature differentiation of progenitor cells, DDX6 regulates the 5′UTR of differentiation inducing transcription factor, KLF4 and degrades its transcripts through association with mRNA degradation proteins. Our results demonstrate that progenitor function is maintained by DDX6 complexes through two distinct pathways which include the degradation of differentiation inducing transcripts as well as promoting the translation of self-renewal and proliferation mRNAs.

DDX6 Represses Aberrant Activation of Interferon-Stimulated Genes

“…To determine whether DDX6 helicase activity is required to prevent immune gene activation, we created a mutant with a single amino acid substitution (DDX6 E247Q ) in the DEAD box RNA helicase domain (DEAD to DQAD) (Mathys et al, 2014; Wang et al, 2015). Genetic complementation of DDX6 E247Q in DDX6 KO cells failed to rescue OAS1 , IFITM1 or VCAM1 expression indicating that the catalytic activity of DDX6 is necessary to repress immune activation (Figures 6E and S6C–E).…”

Evaluation of circulating miRNAs during late pregnancy in the mare

“…Although our down-regulated miRNAs, miR-133b and miR-454, are certainly not pregnancy specific, their down-regulation during pregnancy allows for an increase in the translation of numerous mRNAs, including X-linked RNA binding motif protein (RBMX) which is implicated in regulation of gene transcription and alternative splicing, as well as repairing double-stranded DNA breaks [28, 29] and DEAD (Asp-Glu-Ala-Asp) box helicase 6 (DDX6) which maintains adult progenitor cell function [30]. …”

Cooperativity in RNA–protein interactions: the complex is more than the sum of its partners

“…This data suggests that FMRP binding to the two partners is mutually exclusive, although this notion remains to be proven. Similarly, DDX6 in epidermal progenitors can activate degradation or translation, depending on the mRNA [15 ]. In this manner, collaborative binding explains not only the binding specificity, but also why binding of the same RBP can have diverse -sometimes opposite -effects, depending on the mRNA that is bound and regulated.…”

“…In the proliferation/differentiation decision of mammalian epidermal progenitor cells, for example, the RNA helicase DDX6 binds together with EDC3 to mRNAs that are characterised by G/Crich 5 0 UTRs. However, when in conjunction with YBX1, it associates to mRNAs that have a certain stem-loop in RNP composition determines function Achsel and Bagni 147 Table 1 The RNA-binding properties of RBPs are not selective enough to explain specific (pre-) mRNA binding their 3 0 UTR [15 ]. The outcome for gene expression is diametrically different: while EDC3 with DDX6 induces mRNA degradation, hence inhibiting gene expression, DDX6 with YBX1 induces translation [15 ].…”