Astrocytic Yin Yang 1 is critical for murine brain development and protection against apoptosis, oxidative stress, and inflammation

Abstract

The transcription factor Yin Yang 1 (YY1) is ubiquitously expressed in mammalian cells, regulating the expression of a variety of genes involved in proliferation, differentiation, and apoptosis in a context-dependent manner. While it is well-established that global YY1 knockout (KO) leads to embryonic death in mice and that YY1 deletion in neurons or oligodendrocytes induces impaired brain function, the role of astrocytic YY1 in the brain remains unknown. We investigated the role of astrocytic YY1 in the brain using a glial fibrillary acidic protein (GFAP)-specific YY1 conditional KO (YY1 cKO) mouse model to delete astrocytic YY1. Astrocytic YY1 cKO mice were tested for behavioral phenotypes, such as locomotor activity, coordination, and cognition, followed by an assessment of relevant biological pathways using RNA-sequencing analysis, immunoblotting, and immunohistochemistry in the cortex, midbrain, and cerebellum. YY1 cKO mice showed abnormal phenotypes, movement deficits, and cognitive dysfunction. At the molecular level, astrocytic YY1 deletion altered the expression of genes associated with proliferation and differentiation, p53/caspase apoptotic pathways, oxidative stress response, and inflammatory signaling including NF-κB, STAT, and IRF in all regions. Astrocytic YY1 deletion significantly increased the expression of GFAP as astrocytic activation and Iba1 as microglial activation, indicating astrocytic YY1 deletion activated microglia as well. Accordingly, multiple inflammatory cytokines and chemokines including TNF-α and CXCL10 were elevated. Combined, these novel findings suggest that astrocytic YY1 is a critical transcription factor for normal brain development and locomotor activity, motor coordination, and cognition. Astrocytic YY1 is also essential in preventing pathological oxidative stress, apoptosis, and inflammation.

Yin Yang 1 controls cerebellar astrocyte maturation

“…Yy1 ΔAST mice developed severe motor deficits characterized by a slower velocity (Figure 1g), an increased number of paw slips on a balance beam (Figure 1h, and Supplementary Videos 1-8), and a widened gait (Figure 1i). These findings were similar to those recently reported for YY1 cKO mice generated using the mGfap-cre line 73.12 mice (Pajarillo et al, 2022).…”

“…Although YY1 is ubiquitously expressed in the central nervous system and is critical in neural progenitors (Beagan et al, 2017; Weintraub et al, 2017; Zurkirchen et al, 2019), oligodendrocytes (He et al, 2007), and protects astrocytes against apoptosis, oxidative stress, and inflammation (Pajarillo et al, 2022), its biological functions during astrocyte development are not understood. YY1 is expressed by astrocytes in many brain regions including, cortex, striatum, hippocampus, and cerebellum (Supplementary Figure 1).…”

“…To delineate YY1's roles in astrocytes, we generated conditional knock‐out mice with the Yy1 gene specifically deleted from GFAP + cells ( Yy1 ΔAST ) using the mGfap‐cre line 77.6 mice. Recently, others used the mGfap‐cre line 73.12 mice to delete the Yy1 gene from GFAP + cells (Pajarillo et al, 2022), however, the 73.12 mice also express CRE in adult neural stem cells from the dentate gyrus and subventricular zone as well as in some hippocampal pyramidal, cerebellar granule, and scattered neurons in the midbrain (Garcia et al, 2004). We decided to use the 77.6 mouse line that drives CRE expression mostly in astrocytes, including astrocytes in the cerebellum starting at P7 (Tao et al, 2011), and only in a subpopulation of adult neural stem cells in the subventricular zone.…”

“…Astrocytic YY1 mitigates manganese‐induced neurotoxicity in substantia nigra (Pajarillo et al, 2020). Recently, astrocytic YY1 has been shown to provide protection against apoptosis, oxidative stress, and inflammation (Pajarillo et al, 2022). In this study, we found that YY1 is critical to execute and sustain unique and distinct gene expression programs in subpopulations of cerebellar astrocytes.…”

Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies

“…YY1 in both neuronal and non-neuronal cells is critical for normal brain development and function (for review, see Rylski et al, 2008 ). Astrocytic YY1 regulates oxidative stress, inflammation, and apoptosis in the mouse brain ( Pajarillo et al, 2022b ), and Mn increases YY1 via NF-κB signaling and promotes YY1 binding to the GLT-1/GLAST promoters, resulting in repression of GLT-1/GLAST expression and function in astrocytes ( Karki et al, 2014a ; Pajarillo et al, 2020b ). This Mn effect on YY1 could be closely associated with Mn-induced excitotoxic neuronal injury as reduction of GLT-1/GLAST would accumulate glutamate in the synaptic clefts and overstimulate its receptors.…”