Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner

Zurkirchen, Luis; Varum, Sandra; Giger, Sonja; Klug, Annika; Häusel, Jessica; Bossart, Raphaël; Zemke, Martina; Cantù, Claudio; Atak, Zeynep Kalender; Zamboni, Nicola; Basler, Konrad; Sommer, Lukas

doi:10.1038/s41467-019-09823-5

Cited by 32 publications

(59 citation statements)

References 75 publications

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“…Based on the previous findings that Yy1 may exert its anti-apoptotic function through regulating p53, we checked whether the protein level of p53 was altered in the Yy1 -ablated MHB neuroepithelium [ 11 , 33 – 36 ]. We detected a prominent accumulation of p53 in the cell nucleus of mutant mesencephalon and rhombomere 1 NECs (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This result is similar to the conditional inactivation of Yy1 in E11.5 mouse cortical NPCs. But when Yy1 inactivation occurs at E15.5 late cortical radial glial cells, the expression of Cdc6 is significantly increased [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a group of researchers uncovered that Yy1 exerts a stage-dependent role by regulating metabolic pathways and protein synthesis during cerebral corticogenesis. In the mouse forebrain cortical neural progenitor cells (NPCs), Yy1 controls cell proliferation and survival [ 11 ]. But the mechanism leading to neural developmental defects in other brain regions is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis

Dong

Kwan

2020

Mol Brain

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The highly conserved and ubiquitously expressed transcription factor Yin Yang 1 ( Yy1 ), was named after its dual functions of both activating and repressing gene transcription. Yy1 plays complex roles in various fundamental biological processes such as the cell cycle progression, cell proliferation, survival, and differentiation. Patients with dominant Yy1 mutations suffer from central nervous system (CNS) developmental defects. However, the role of Yy1 in mammalian CNS development remains to be fully elucidated. The isthmus organizer locates to the mid-hindbrain (MHB) boundary region and serves as the critical signaling center during midbrain and cerebellar early patterning. To study the function of Yy1 in mesencephalon/ rhombomere 1 (mes/r1) neuroepithelium development, we utilized the tissue-specific Cre-LoxP system and generated a conditional knockout mouse line to inactivate Yy1 in the MHB region. Mice with Yy1 deletion in the mes/r1 region displayed cerebellar agenesis and dorsal midbrain hypoplasia. The Yy1 deleted neuroepithelial cells underwent cell cycle arrest and apoptosis, with the concurrent changes of cell cycle regulatory genes expression, as well as activation of the p53 pathway. Moreover, we found that Yy1 is involved in the transcriptional activation of Wnt1 in neural stem cells. Thus, our work demonstrates the involvement of Yy1 in cerebellar agenesis and the critical function of Yy1 in mouse early MHB neuroepithelium maintenance and development.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis

Dong

Kwan

2020

Mol Brain

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“…Our findings complement a previous study that identified YY1 as an upstream regulator of an MDD-associated transcriptional program in whole blood samples generated from MDD patients that also found that Yy1 expression is negatively correlated with MDD status 51 We show that inactivation of YY1 in PFC excitatory neurons alone did not impair behavior in male and female mice but rendered them more sensitive to stress. Although YY1 is constitutively expressed into adulthood, a recent study has shown that YY1 function is most critical during early cortical development and that neuronal dependence on YY1 decreases with age 61 . Our study demonstrates that loss of YY1 in cortical excitatory neurons does not drive functional impairment of the PFC but impairs neuronal adaptation to environmental stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…We next sought to assess whether the dysregulated expression of genes shared between Yy1-exKO aCUS and CUS animals could be directly caused, in part, by decreased YY1 function. We surveyed the genomic landscape at the shared DEGs, Nr3c1 and Fos, for enrichment of YY1, using publicly available YY1 chromatin immunoprecipitation-sequencing (ChIP-seq) data obtained from mouse cortical cells 61 . We also examined H3K27ac, a chromatin mark associated with enhancers and active promoters, in adult cortical excitatory neurons 62 .…”

Section: Given That Our Experimental and Computational Analyses Uncovmentioning

confidence: 99%

Stress-induced epigenetic regulation of transcription in neocortical excitatory neurons drives depression-like behavior

Kwon

Zhao

et al. 2020

Preprint

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ABSTRACTProlonged stress exposure is a major risk factor for the development of depression and comorbid anxiety. Efforts to understand how recurrent stress induces behavioral maladaptation have largely concentrated on the neuronal synapse with limited understanding of the underlying epigenetic mechanisms. Here, we performed complementary bulk nuclei- and single-nucleus transcriptome profiling and mapped fine-scale chromatin architecture in mice subjected to chronic unpredictable stress (CUS) to identify the cell type-specific epigenetic alterations that drive complex behavior. We find that neocortical excitatory neurons are particularly vulnerable to chronic stress and acquire signatures of transcription and chromatin configuration that denote reduced neuronal activity and expression of Yin Yang 1 (YY1). Selective ablation of YY1 in excitatory neurons of the prefrontal cortex (PFC) enhances stress sensitivity in mice, inducing depressive- and anxiety-related behaviors and deregulating the expression of stress-associated genes following an abbreviated stress exposure. Notably, we find that loss of YY1 in PFC excitatory neurons provokes more maladaptive behaviors in stressed females than males. These findings demonstrate how chronic stress provokes maladaptive behavior by epigenetically shaping excitatory neurons in the PFC, identifying a novel molecular target for therapeutic treatment of stress-related mood and anxiety disorders.

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

Pajarillo

Nyarko-Danquah

Digman

et al. 2022

Glia

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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.

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Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner

Cited by 32 publications

References 75 publications

Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis

Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis

Stress-induced epigenetic regulation of transcription in neocortical excitatory neurons drives depression-like behavior

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

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