A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-Mediated Exhaustion

Abstract

Disrupting the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) leads to bone marrow failure or hematologic malignancy. However, how HSCs sustain their quiescent state and avoid type I interferon (IFN)-mediated exhaustion remains elusive. Here we defined a circular RNA that we named cia-cGAS that was highly expressed in the nucleus of long-term (LT)-HSCs. Cia-cGAS deficiency in mice caused elevated expression of type I IFNs in bone marrow and led to decreased numbers of dormant LT-HSCs. Under homeostatic conditions, cia-cGAS bound DNA sensor cGAS in the nucleus to block its synthase activity, thereby protecting dormant LT-HSCs from cGAS-mediated exhaustion. Moreover, cia-cGAS harbored a stronger binding affinity to cGAS than self-DNA did and consequently suppressed cGAS-mediated production of type I IFNs in LT-HSCs. Our findings reveal a mechanism by which cia-cGAS inhibits nuclear cGAS by blocking its enzymatic activity and preventing cGAS from recognizing self-DNA to maintain host homeostasis.

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

“…Multiple concurrent mechanisms are likely in play. One example is the recently reported circular RNA cia‐cGAS that binds and blocks cGAS (Xia et al , ). Additionally, we posit that in contrast to naked dsDNA, binding to dsDNA in the context of the complex chromatin matrix may be unfavorable for cGAS synthase activity.…”

Past, present, and future of circ RNA s

“…The production of this circRNA was inhibited by deletion of the reverse complementary sequence in the downstream flanking intron using Cas-9 (Xia et al, 2018). The production of this circRNA was inhibited by deletion of the reverse complementary sequence in the downstream flanking intron using Cas-9 (Xia et al, 2018).…”

“…A subset of circRNA produces proteins in the fly brain and in murine and human cells Pamudurti et al, 2017;Yang et al, 2017), and others seem to be related to the immune response (Li et al, 2017a;Liu et al, 2019). Several reports demonstrated in vivo functions for circRNAs in the mouse and fly brains, as well as in bone marrow (Piwecka et al, 2017;Kleaveland et al, 2018;Xia et al, 2018;Data ref: Pamudurti et al, 2018). In addition, a number of studies suggest an association between circRNAs and cancer (reviewed in Kristensen et al, 2018;Patop & Kadener, 2018).…”

Two to Tango: Dialog between Immunity and Stem Cells in Health and Disease

“…Because many of these receptors have endogenous ligands that are available even in the absence of infections, stem cells have installed regulatory machineries to avoid aberrant activation by innate sensors. Dormant HSCs for example, express the circular RNA cis-GAS, with higher affinity for cGAS than its activating ligand, enabling calibration of HSC sensitivity to endogenous dsDNA and thereby preventing exhaustion (Xia et al, 2018) (Figure 4A). …”