Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

Abstract

Objective: Microglia, the prototypical innate immune cells of the central nervous system (CNS), are highly plastic and assume their phenotypes dependent on intrinsically genetic, epigenetic regulation or extrinsically microenvironmental cues. Microglia has been recognized as key regulators of neural stem/progenitor cells (NSPCs) and brain functions. Chromatin accessibility is implicated in immune cell development and functional regulation. However, it is still unknown whether and how chromatin remodelling regulates the phenotypic plasticity of microglia and exerts what kind of effects on NSPCs. Methods:We investigated the role of chromatin accessibility in microglia by deleting chromatin remodelling gene Arid1a using microglia-specific Cx3cr1-cre and Cx3cr1-CreERT2 mice. RNA-seq and ATAC-seq were performed to dissect the molecular mechanisms. In addition, we examined postnatal M1/M2 microglia polarization and analysed neuronal differentiation of NSPCs. Finally, we tested the effects of microglial Arid1a deletion on mouse behaviours.Results: Increased chromatin accessibility upon Arid1a ablation resulted in enhanced M1 microglial polarization and weakened M2 polarization, which led to abnormal neurogenesis and anxiety-like behaviours. Switching the polarization state under IL4 stimulation could rescue abnormal neurogenesis, supporting an essential role for chromatin remodeler ARID1A in balancing microglial polarization and brain functions.Conclusions: Our study identifies ARID1A as a central regulator of microglia polarization, establishing a mechanistic link between chromatin remodelling, neurogenesis and mouse behaviours, and highlights the potential development of innovative therapeutics exploiting the innate regenerative capacity of the nervous system. | INTRODUCTIONMicroglia, the only resident immune cells that enduringly reside in the central nervous system (CNS), 1 play vital roles in regulating the homeostasis of CNS. 2 In the past years, studies on microglia have expanded from investigating their immunological functions as resident macrophages of brain and mediators of neuroinflammation, injury, neurodegeneration to understanding their origins and functions involved in complex neurodevelopmental programs in the CNS. [3][4][5][6] Evidence has shown that microglia modulate neurogenesis and synaptic pruning, during which they interact with neural stem/progenitor cells (NSPCs) or neurons to provide trophic support, respond to

Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System

“…Hence, to compare our results with experimental data, we searched the literature for any evidence supporting the immune modulatory function of the genes related to microglia. Of the thirteen genes, we found clear evidence in the literature for eight genes on their relevance in microglial function and neuronal inflammation (Mef2a [26], Hdac11 [27,28], Smad3 [29], Mef2c [30], Arid1a [31,32], Zfhx3 [33,34], Ets1 [35], and Jun [36]). Four genes were mentioned in experiments on microglial inflammation (Xrcc5 [37,38], Zfp191 [39], Prdm1 [40], and Usf2 [41]), whereas no information was found in the literature for only two genes (Znf383 and Nfrkb).…”

Origin and Emergence of Microglia in the CNS—An Interesting (Hi)story of an Eccentric Cell

“…These findings underscored the potential role of miR-124 as a regulator of microglial surveillance in the CNS [ 74 ]. Microglial polarization is regulated by ARID1A, an epigenetic subunit of the SWI/SNF chromatin-remodeling complex, through alterations of the chromatin state in microglia [ 75 , 76 ]. The migration of microglial cells also seemed to be affected by PGRN, because its knockdown resulted in a failure of microglial precursors to colonize the embryonic retina [ 77 ].…”

Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

“…In microglia, the loss of Arid1a leads to the perturbation of microglial homeostasis through disruption of genome-wide H3K9me3 occupancy and changes of the chromatin landscape of regulatory elements that influence the switching of microglial states [ 25 ]. Furthermore, microglia-specific Arid1a ablation enhances M1 microglial polarization and weakens M2 polarization, which may explain anxiety-like behaviors in these animals [ 26 ]. In the liver, hepatocyte-specific abolition of Arid1a impairs liver regeneration through down-regulation of chromatin accessibility and gene expression associated with injury-induced liver-progenitor-like cells [ 27 ].…”